Detection of fluidic current generated by rotating magnetic particles

ABSTRACT

Some embodiments provide a system for external manipulation of magnetic nanoparticles in vasculature using a remotely placed magnetic field-generating stator. In one embodiment, the systems and methods relate to the control of magnetic nanoparticles in a fluid medium using permanent magnet-based or electromagnetic field-generating stator sources. Such a system can be useful for increasing the diffusion of therapeutic agents in a fluid medium, such as a human circulatory system, which can result in substantial clearance of fluid obstructions, such as vascular occlusions, in a circulatory system resulting in increased blood flow. Magnetic nanoparticles are provided having a non-specialized chemical coating facilitating association with a chemical composition by a user before infusion. Systems are provided for delivering a consistent infusion mass of magnetic nanoparticles to a patient.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/400,999, having a 371(c) filing date of Nov. 13, 2014; which is a 371National Phase of International Application No. PCT/US2013/040789, filedMay 13, 2013, which claims priority to U.S. application Ser. No.61/695,257, filed Aug. 30, 2012, the entire contents of which are herebyincorporated herein by reference. International Application No.PCT/US2013/040789 is also a continuation-in-part application of U.S.application Ser. No. 13/471,871, filed May 15, 2012, now U.S. Pat. No.8,308,628; and of U.S. application Ser. No. 13/471,908, filed May 15,2012, now U.S. Pat. No. 8,313,422; the entire contents of each of whichare hereby incorporated herein by reference.

FIELD

This disclosure generally relates to systems and methods forfacilitating introduction and external manipulation of magneticparticles (e.g., nanoparticles) within vasculature of a circulatorysystem for the treatment of various conditions.

BACKGROUND

The treatment of fluid obstructions in the circulatory system, includingvascular occlusions in vessels of the brain and vessels of theextremities, has included the use of drugs that can dissolve theobstructions and the use of obstruction removal devices. However,side-effects of such drugs are difficult to control and such obstructionremoval devices often involve invasive procedures that cause unintendedor secondary tissue damage. In addition, both the use of drugs at normaldosages and the use of invasive thrombectomy devices can result indeath.

SUMMARY

In several embodiments, a therapeutic system is provided comprising amagnet having a magnetic field and a gradient for controlling magneticrotors in a circulatory system, and a controller for positioning androtating or oscillating the magnetic field and the gradient in a mannerto agglomerate and move the magnetic rotors with respect to atherapeutic target in the circulatory system. Using the therapeuticsystem, contact of the therapeutic target with a pharmaceuticalcomposition or other agent in the circulatory system is increasedaccording to one embodiment. In various embodiments, the pharmaceuticalcomposition is attached to the magnetic rotor or otherwiseco-administered, and in other embodiments is administered to thecirculatory system separate from the magnetic rotors. In certainembodiments, the pharmaceutical composition is a thrombolytic drug, suchas tissue plasminogen activator (tPA).

Therapeutic targets of the system can include fluid obstructions suchas, but not limited to, atherosclerotic plaques, fibrous caps, fattybuildup, coronary occlusions, arterial stenosis, arterial restenosis,vein thrombi, arterial thrombi, cerebral thrombi, embolisms (e.g.,pulmonary embolisms), hemorrhages, very small vessels, blood clots inthe eye, vascular tumors (e.g., hemangioma, lymphangioma,hemangioendothelioma, Kaposi sarcoma, angiosarcoma, hemangioblastoma),other fluid obstructions, and/or any combination of these. Vasculartherapeutic targets may also include arteriovenous malformations in thearteries or veins of the brain or other organs (e.g., true arteriovenousmalformations, occult or cryptic or cavernous malformations, venousmalformations, hemangioma, dural fistulas). Therapeutic targets of thesystem can also include any organ or tissue of the body (e.g., heart,brain, legs, arms, lungs, vestibular system, tumors or cancerous tissue)or the vascular associated with the organ or tissue). In someembodiments, therapeutic targets can be targets identified for stem celland/or gene therapy (e.g., gene delivery). In some embodiments, themagnetic rotors can be delivered within spinal fluid (e.g.,cerebrospinal fluid). In various embodiments, the circulatory system isvasculature of a subject (e.g., a human or animal patient).

In various embodiments, the therapeutic system comprises a permanentmagnet coupled to a motor and the controller controls a motor toposition the magnet at an effective distance and an effective plane withrespect to the therapeutic target and rotates the magnet at an effectivefrequency to address the therapeutic target by directing the magneticrotors toward the therapeutic target. In various embodiments, thetherapeutic system comprises an electromagnet having a magnetic fieldstrength and magnetic field polarization driven by electrical currentand the controller rotates the magnetic field of the electromagnet byadjusting the electrical current.

In several embodiments, the therapeutic system includes a display (e.g.,monitor or screen) for viewing the magnetic rotors and/or therapeutictarget and a user interface (including a touchscreen display, keyboard,mousepad, joystick, and/or other input means) for controlling themagnetic rotors, such that a user can control the magnetic rotors toclear, remove, or reduce in size a therapeutic target by adjusting afrequency of the rotating magnetic field, an orientation plane of therotating magnetic field with respect to the therapeutic target, and/or adistance of the rotating magnetic field with respect to the therapeutictarget. In various embodiments, the therapeutic target is a thrombosis,embolism or clot in a human blood vessel having low blood flow or noblood flow. In various embodiments, the magnetic rotors are magneticnanoparticles injected into the circulatory system. The magneticnanoparticles can be coated or uncoated.

In several embodiments, the magnetic rotors move through the fluid in acircular motion by repeatedly walking end over end along the bloodvessel away from the magnetic field in response to the rotation of therotors caused by torque exerted on the rotors by a rotating magneticfield and an attractive force (e.g., a directed gradient) of themagnetic field and then flowing back through the fluid towards themagnetic field in response to the rotation of the rotors and theattractive force (e.g., directed gradient) of the magnetic field.

In some embodiments, a therapeutic system is provided for increasingfluid flow in a circulatory system comprising a magnet having a magneticfield for controlling a magnetic tool in the fluid and a controllerconfigured to position and rotate the magnetic field with respect to thetherapeutic target to rotate an abrasive surface of the magnetic tooland maneuver the rotating abrasive surface to contact and increase fluidflow through or around the therapeutic target. In various embodiments,the circulatory system comprises vasculature of a subject, such as ahuman patient. In various embodiments, the magnetic tool is coupled to astabilizing rod and the magnetic tool rotates about the stabilizing rodin response to the rotating magnetic field. In some embodiments, themagnetic tool comprises an abrasive cap affixed to a magnet whichengages and cuts through the therapeutic target. In some embodiments,the controller positions the magnetic tool at a target point on thetherapeutic target and rotates the magnetic tool at a frequencysufficient to cut through the therapeutic target. The magnet can bepositioned so that poles of the magnet periodically attract the opposingpoles of the magnetic tool during rotation, such that the magnetic toolis pushed towards the therapeutic target by a stabilizing rod upon whichthe magnetic tool rotates. In some embodiments the magnet is positionedso that the poles of the magnet continuously attract the opposing polesof the magnetic tool during rotation, and the magnetic tool is pulledtowards the therapeutic target by an attractive force (e.g., a directedgradient) of the magnet.

In some embodiments, a system is provided for increasing fluid flow in acirculatory system comprising a magnet having a magnetic field forcontrolling magnetic rotors in the fluid. In some embodiments, thesystem comprises a display for displaying, to a user, the magneticrotors and the therapeutic target in the fluid, and a controller that,in response to instructions from the user, controls the magnetic fieldto position the magnetic rotors adjacent to the therapeutic target,adjust an angular orientation of the magnetic rotors with respect to thetherapeutic target, and rotate and move the magnetic rotors through thefluid in a generally circular or oscillatory motion to mix the fluid andsubstantially clear the therapeutic target.

In various embodiments, the display (e.g., screen, monitor) displaysreal time (e.g., streaming) video of the magnetic rotors (e.g.,nanoparticles) and the therapeutic target (e.g., clot). In someembodiments, the display superimposes a graphic representative of arotation plane of the magnetic field and another graphic representativeof the attractive force (e.g., directed gradient) of the magnetic fieldon the real-time video on the display. In some embodiments, the magnetis a permanent magnet coupled to a motor and a movable arm. In someembodiments, the controller comprises a remote control device for a userto manipulate the position, rotation plane and/or rotation frequency ofthe magnetic field with respect to the therapeutic target. The remotecontrol device can be used to manipulate the position and rotation planein one, two, or three dimensions.

In some embodiments, the real time video can correspond to imagesreceived from an imaging system, such as a transcranial Doppler imagingsystem, a PET imaging system, an x-ray imaging system, an MRI imagingsystem, a CT imaging system, an ultrasound imaging system, and/or thelike. In some embodiments, the imaging system is relatively immune fromthe magnetic fields present when the control system is in operation. Thecontrol system can receive images from the imaging system, register theimages, and present them to the user to provide real-time feedback as tothe position of the magnetic nanoparticles, vasculature of the patient,and/or the location of the target object. In some embodiments, imagingthe magnetic nanoparticles can provide information about drug infusionand/or dose concentration. Using this information, the control of themagnetic nanoparticles can be altered between a mode where nanoparticlesare collected and a mode where nanoparticles are vortexed, or made tofollow a substantially circular path and/or oscillating path pattern tobetter mix the chemical agent within the vasculature, thereby enhancingdiffusion of the chemical agent to the location of the therapeutictarget and/or to enhance interaction of the chemical agent with thetherapeutic target. In some embodiments, the magnetic nanoparticlescomprise a contrast agent or tracer and can be correlated to a drug orchemical agent. In some embodiments, the magnetic nanoparticles are usedas an indication of the amount of diffusion within the vasculature in aregion of the therapeutic target.

In some embodiments, the display adjusts the graphics in response toinstructions received from the user through the remote control device.In various embodiments, the magnet is an electromagnet coupled to amotor and a movable arm and the controller performs image processing toidentify the location, shape, thickness and density of the therapeutictarget. In some embodiments, the controller automatically manipulatesthe movable arm to control the position, rotation plane and/or rotationfrequency of the magnetic field to clear the therapeutic target. In someembodiments, the automatic manipulation controls the nanoparticlesaccording to a navigation route designated or programmed by a user. Theuser can determine and input the navigation route and make adjustmentsduring particle infusion or at any other time during a therapeuticprocedure. In some embodiments, the navigation route is automaticallycalculated and/or adjusted by a controller of the therapeutic system.

In some embodiments, the magnet is stowed in a substantially shieldedenclosure, thereby substantially reducing or preventing magnetic fieldsof one or more magnets of the system from having an effect on persons oritems outside the system. For example, the system can include anenclosure made out of a suitable shielding material (e.g., iron). Theautomatic manipulation provided by the controller can move the one ormore magnets of the system into the shielded enclosure when not in use.

In some embodiments, the therapeutic system provides real-timeinformation for the improved control of movement of the magneticnanoparticles. The magnetic nanoparticles can be configured to bedetectable with an imaging modality. For example, the magneticnanoparticles may be attached to a contrast or nuclear agent to bevisible using an x-ray-based system or PET scanner, respectively. Otherimaging modalities can include Doppler imaging (e.g., transcranialDoppler), which may detect the fluidic current through vasculaturecreated by the magnetic nanoparticles, or ultrasound-based diagnosticimaging systems, which may provide direct two-dimension orthree-dimensional imaging. Combining the control system with an imagingsystem can provide the ability to track the infusion of the chemicaladjunct in real-time into low-blood-flow lumens. By manipulating themagnetic system, three-degrees of control of the infused magneticnanoparticles can be achieved, thereby improving the ability to directthe therapy.

The imaging modality can be any modality, including imaging modalitiescapable of resolving a device or chemical agent which is affected by thefluidic current generated by the magnetic nanoparticles. The imagingmodality, in one embodiment, images an area of interest and providesmetric information. The therapeutic system can include a communicationmodule for communicating imaging data to an external device (such as adisplay device or a storage device). The therapeutic system can includea registering module for registering the reference frame of the image tothe reference frame of the magnetic system. The system can then receivethe image, register the image, track the magnetic nanoparticles, andprovide a means of directing the nanoparticles to be navigated along adesired path, either by an operator or automatically by a controller ofa computing device. The imaging data can be two- or three-dimensionaldata. Three-dimensional information may be advantageous wherenavigational control occurs in three dimensions. In some embodiments,the control of the magnetic nanoparticles occurs remotely using thesystems described herein.

In certain embodiments, the magnetic rotors can be formed by magneticnanoparticles which combine in the presence of the magnetic field (e.g.,agglomerate to form a chain of nanoparticles). In some embodiments, thefluid is a mixture of blood and a therapeutic agent (e.g., athrombolytic drug such as tPA), the blood and therapeutic agent beingmixed by the generally circular or oscillatory motion of the magneticnanoparticles to erode and clear a therapeutic target (such as athrombus or clot). In some embodiments, the generally circular oroscillatory motion of the magnetic nanoparticles can redirect thetherapeutic agent from a high flow blood vessel to a low flow bloodvessel containing the therapeutic target. In some embodiments, themagnetic nanoparticles formed in the presence of the magnetic field canbe used to create blood flow currents which direct the therapeutic agentto a targeted location.

In one embodiment, a method is provided for increasing fluid flow in acirculatory system comprising administering a therapeutically effectiveamount of magnetic rotors (e.g., magnetic nanoparticles) to thecirculatory system of a patient having a fluid obstruction and applyinga rotating magnetic field to the patient with a permanent magnet or anelectromagnet, the rotating magnetic field and a directed gradient beingconfigured to control the magnetic rotors in a circulatory system, andusing a controller for positioning and/or rotating the magnetic fieldand the magnetic gradient in a manner to agglomerate and move themagnetic rotors with respect to a therapeutic target in the circulatorysystem of the patient, wherein contact of the therapeutic target with atherapeutic agent (e.g., a pharmaceutical composition) in thecirculatory system is increased and fluid flow is increased. In someembodiments, positioning and rotating the field and the gradient toagglomerate and move the magnetic rotors creates or increases blood flowcurrents which can be used to direct the therapeutic agent (e.g., apharmaceutical composition, chemical adjunct, stem cell, geneticmaterial or other biologic, etc.) to the therapeutic target (e.g., clot,thrombus or blockage). In some embodiments, the blood flow currents canadvantageously be caused by magnetic nanoparticles combined to formnanoparticle rods having a length between 0.1 and 2 millimeters whenexposed to a rotating time-varying magnetic field magnitude of between0.01 Tesla and 0.1 Tesla and a magnetic gradient strength of between0.01 Tesla/meter and 5 Tesla/meter and wherein the rotation frequency isbetween 1 Hz and 10 Hz (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Hz).

The therapeutic agent (e.g., pharmaceutical composition, chemicaladjunct, thrombolytic drug), according to several embodiments, can beattached to the magnetic rotor or to the individual magneticnanoparticles comprising the magnetic rotor. For example, the magneticnanoparticles can include a coating to facilitate attachment oftherapeutic agents. The therapeutic agent can be administered to thecirculatory system of the patient separate from the magnetic rotors.

The therapeutic target, according to several embodiments, can be athrombosis (e.g., a clot) in a human blood vessel (e.g., a blood vesselof the brain or leading to the brain or a blood vessel in a leg). Insome embodiments, the magnetic rotors can be formed from magneticnanoparticles injected into the circulatory system. The therapeutictarget, in one embodiment, is a full or partial blockage of a veinbivalve. In certain embodiments, the magnetic rotors move through thefluid in a generally circular or oscillatory motion by repeatedlyrotating end over end in response to a time-varying magnetic field and amagnetic gradient resulting in motion away from the magnetic fieldthrough frictional forces between the magnetic rotors and a wall of avein and flowing back through the fluid towards the magnetic field inresponse to the rotation of the rotors and the attractive force of themagnetic field.

The magnetic rotor, according to several embodiments, is a magneticnanoparticle of a diameter greater than or equal to about 10 nm and/orless than or equal to about 200 nm, including but not limited to fromabout 10 nm to about 150 nm, from about 15 nm to about 100 nm, fromabout 20 nm to about 60 nm, from about 20 nm to about 100 nm, from about30 nm to about 50 nm, overlapping ranges thereof, less than 200 nm, lessthan 150 nm, less than 100 nm, less than 60 nm. In some embodiments, thetherapeutic target is a vascular occlusion in the patient's head or avascular occlusion in the patient's leg.

In some embodiments, a method is provided for increasing drug diffusionin a circulatory system is provided. The method can compriseadministering a therapeutically effective amount of magnetic rotors tothe circulatory system of a patient. In some embodiments, the methodcomprises applying a magnet to the patient, the magnet having a magneticfield and a gradient for controlling the magnetic rotors in thecirculatory system. In some embodiments, the method comprises using acontroller configured to position and rotate the field and the gradientin a manner to agglomerate and move the magnetic rotors with respect toa therapeutic target in the circulatory system of the patient. In someembodiments, diffusion of a therapeutic agent (e.g., a pharmaceuticalcomposition) in the circulatory system at the therapeutic target isincreased as a result of the presence and movement of the magneticrotors.

In accordance with several embodiments, a system is disclosed fordelivering agents that are not readily dispersed in a solution. Thesystem, in use, can ensure predictable delivery of the agents in thesolution. In one embodiment, the system comprises a pump that, in use,pushes a solvent through tubing towards a subject. In one embodiment,the system comprises an inlet tubing coupled to the pump that, in use,transports the solvent from the pump. In one embodiment, the systemcomprises a reservoir coupled to the inlet tubing that, in use, holds atleast a portion of a solute comprising the agents that are not readilydispersed in the solution. In one embodiment, the system comprises anagitating mechanism coupled to the reservoir that, in use, agitates thesolvent and the solute to create a dispersed solution. In oneembodiment, the system comprises an outlet tubing coupled to thereservoir that, in use, transports the dispersed solution to thesubject. In one embodiment, the solute comprises magnetic particles ornanoparticles. In one embodiment, the outlet tubing comprises micro-boretubing. In one embodiment, the system comprises a diaphragm in thereservoir that, in use, pushes a solution in the reservoir into theoutlet tubing when the solution from the pump enters the reservoirthrough the inlet tubing. In one embodiment, the system comprises tubingwithin the reservoir that, in use, holds at least a portion of thesolution to be dispersed. In one embodiment, the system includes aliquid or gel in the reservoir that, in use, transmits energy from theagitating mechanism to the tubing within the reservoir.

In accordance with several embodiments, the system comprises a supportstructure. In one embodiment, the reservoir comprises an IV drip bagcoupled to the support structure that, in use, holds at least a portionof the solution with the agents that are not readily dispersed. In oneembodiment, the agitating mechanism is coupled to the IV drip bag that,in use, agitates the solution to create or maintain a dispersedsolution. In one embodiment, the system comprises an outlet tube coupledto the IV drip bag that, in use, transports the dispersed solution tothe subject. In one embodiment, the system comprises a drip chamberhaving a conical bottom coupled to the IV drip bag and the outlet tube.

In accordance with several embodiments, the system comprises a syringepump that, in use, controls dispersal of contents of one or moresyringes. In one embodiment, the system comprises a plurality ofsyringes coupled to the syringe pump. In one embodiment, the systemcomprises a plurality of outlet tubes coupled to the plurality ofsyringes. In one embodiment, the system comprises a manifold coupled tothe plurality of outlet tubing that, in use, joins the solution from oneor more of the plurality of syringes for delivery to a subject. In oneembodiment, the system comprises a manifold valve that, in use, controlsfluid flow along the manifold. The system can comprise an outlet tubethat, in use, delivers the solution from the manifold to the subject. Inone embodiment, the system comprises an outlet valve that, in use,controls fluid flow from the manifold to the outlet tube. In oneembodiment, the system comprises an agitation mechanism coupled to thesyringe pump that, in use, agitates the plurality of syringessufficiently to create or maintain a dispersed solution in the pluralityof syringes.

In one embodiment, the syringe pump transfers a portion of the solutionfrom a first syringe to a second syringe by dispersing the solution fromthe first syringe and collecting the solution with the second syringesuch that the movement of the solution from the first syringe to thesecond syringe agitates the solution to maintain dispersion. In oneembodiment, at least one of the plurality of syringes contains a salinesolution. In one embodiment, the manifold valve controls a flow of thesaline solution along the manifold. In one embodiment, the at least onesyringe with the saline solution disperses the saline solution to flushthe outlet tube after delivery of the solution to the subject. In oneembodiment, during a dynamic mixing phase, the manifold valve is closedto substantially prevent the saline solution from exiting a salinesolution portion of the manifold, and the outlet valve is closed tosubstantially prevent the solution to flow from the manifold to theoutlet tube. In one embodiment, during a solution distribution phase,the manifold valve is closed to substantially prevent the salinesolution from exiting a saline solution portion of the manifold, and theoutlet valve is open to allow the solution to flow from the manifold tothe outlet tube. In one embodiment, during a flushing phase, themanifold valve is open to allow the saline solution to flow from themanifold to the outlet tube.

In one embodiment, the agitating mechanism is an ultrasound transducerthat, in use, produces timed ultrasound pulses sufficient to maintaindispersion in the solution. In one embodiment, the agitating mechanismis a magnet that, in use, produces a time-varying magnetic fieldsufficient to maintain dispersion of magnetic particles in the solution.The magnetic field can vary with a frequency greater than or equal toabout 1 Hz and/or less than or equal to about 100 Hz, greater than orequal to about 5 Hz and/or less than or equal to about 50 Hz, and/orgreater than or equal to about 10 Hz and/or less than or equal to about30 Hz, greater than or equal to about 1 Hz and/or less than or equal toabout 10 Hz, or overlapping ranges thereof, less than 100 Hz, less than50 Hz, less than 30 Hz, less than 10 Hz.

In one embodiment, the agitating mechanism is a mechanically actuatedbar that squeezes a portion of the IV drip bag or reservoir in a timed,continuous, periodic, and/or rhythmic manner. The mechanical agitationcan be repeated with a frequency greater than or equal to about 0.1 Hzand/or less than or equal to about 5 Hz, or a frequency greater than orequal to about 0.25 Hz and/or less than or equal to about 3 Hz, oroverlapping ranges thereof. In one embodiment, the agitating mechanismis an air bladder (e.g., a balloon) coupled to a compressor that pulsesair to the air bladder, pauses to allow the air from the air bladder tobleed into the IV drip bag or reservoir, and then repeats. In oneembodiment, the agitating mechanism is a mechanical vortexer that, inuse, mechanically agitates the particle container.

In one embodiment, the micro-bore tubing can have an inner diametersufficiently small to maintain dispersion of the solution duringtransport to the subject. The inner diameter of the micro-bore tubingcan be between 0.01 inches and 0.10 inches (e.g., less than or equal toabout 0.05 inches, less than or equal to about 0.048 inches, less thanor equal to about 0.034 inches, and/or less than or equal to about 0.023inches). The micro-bore tubing can be at least about 40 inches in lengthand/or less than or equal to about 180 inches in length, at least about50 inches in length and/or less than or equal to about 100 inches inlength, or at least about 57 inches in length and/or less than or equalto about 61 inches in length, or overlapping ranges thereof. Themicro-bore tubing can have a volume that is at least about 0.3 mL and/orless than or equal to about 2.0 mL, at least about 0.4 mL and/or lessthan or equal to about 1.8 mL, at least about 0.5 mL and/or less than orequal to about 1.7 mL, overlapping ranges thereof, less than 0.3 mL, orgreater than 2.0 mL.

In accordance with several embodiments, a magnetomotive system isdisclosed that is portable and that increases fluid flow through anobstructed blood vessel by wireless manipulation of magneticnanoparticles. In one embodiment, the system comprises a magnet pod. Inone embodiment, the system comprises a headrest rotatably coupled to themagnet pod. In one embodiment, the system comprises a rail attachmentattached to the magnet pod that, in use, substantially secures themagnet pod to a bed or other similar structure. In one embodiment, thesystem comprises a magnet coupled to the magnet pod, the magnet having amagnetic field and a directed magnetic gradient that, in use, providesexternal magnetomotive control of magnetic nanoparticles introducedwithin vasculature of a subject. The magnet can comprise one or morepermanent magnets or electromagnets.

In one embodiment, the system comprises a controller that, in use,causes the magnet pod to manipulate the magnetic field, the directedmagnetic gradient, or both to create a time-varying magnetic field andto control the direction and magnitude of the magnetic gradient of themagnet. In one embodiment, the system manipulates the magnetic field,the directed magnetic gradient, or both causing magnetic nanoparticlespresent within the vasculature to agglomerate into a plurality ofmagnetic nanoparticle rods and causes the magnetic nanoparticle rods totravel through fluid within the vasculature in a generally circulatingor oscillating motion by repeatedly walking end over end away from themagnetic field in response to rotation of the magnetic nanoparticle rodsand the magnetic gradient and flowing back through the fluid towards themagnetic field in response to the rotation of the magnetic nanoparticlerods and the magnetic gradient. In one embodiment, the generallycircular or oscillatory motion of travel of the magnetic nanoparticlesincreases exposure of a fluid obstruction within a blood vessel of thevasculature to a thrombolytic agent present in the blood vessel andaccelerates action of the thrombolytic agent on the fluid obstruction.In one embodiment, the headrest, in use, defines a position and attitudeof a subject's head in relation to the magnet pod.

In accordance with several embodiments, a magnetomotive system forwireless manipulation of magnetic nanoparticles comprises an imagingmodule that, in use, receives imaging data from an imaging system,wherein the imaging data comprises information derived from an imagingmodality that, in use, provides information about vasculature of asubject, relative position of the magnetic nanoparticles, or both. Inone embodiment, the magnetomotive system comprises a registration modulethat, in use, registers a reference frame of the magnetomotive system toa reference frame of the imaging system such that the received imagingdata is mapped to positions relative to the magnetomotive system. In oneembodiment, the magnetomotive system comprises a tracking module that,in use, identifies the magnetic nanoparticles within the receivedimaging data and determines a position of the magnetic nanoparticlesrelative to the magnetomotive system.

In one embodiment, the magnetomotive system comprises a navigationmodule that, in use, plans a navigation path from the position of themagnetic nanoparticles to a desired location within the subject based onthe received imaging data. In one embodiment, the magnetomotive systemcomprises a controller that, in use, causes the magnetomotive system tomanipulate at least one of a position and an orientation of a magnet tocreate a time-varying magnetic field and to control a direction and amagnitude of a magnetic gradient of the magnet. In one embodiment, thetime-varying magnetic field, the direction of the magnetic gradient, andthe magnitude of the magnetic gradient navigates the magneticnanoparticles according to the navigation path by causing the magneticnanoparticles present within the vasculature to agglomerate into aplurality of magnetic nanoparticle rods and causing the magneticnanoparticle rods to travel through fluid within the vasculature in agenerally circulating or oscillating motion as described herein toincreases exposure of a fluid obstruction within a blood vessel of thevasculature to a thrombolytic agent present in the blood vessel and toaccelerate action of the thrombolytic agent on the fluid obstruction.The magnetic nanoparticles can facilitate treatment or clearing of thefluid obstruction without contacting the fluid obstruction. In someembodiments, the magnetic nanoparticles are non-abrasive. In someembodiments, the nanoparticle rods are substantially elliptical.

In accordance with several embodiments, a magnetomotive system forincreasing fluid flow through an obstructed blood vessel by wirelessmanipulation of magnetic nanoparticles comprises a robotic arm with aproximal end and a distal end. The robotic arm can be configured tocontrol a position of the distal end of the robotic arm along threedimensions and to control an orientation of the distal end of therobotic arm along three axes of rotation. In one embodiment, themagnetomotive system comprises a magnet coupled to the distal end of therobotic arm, the magnet producing a magnetic field and a directedmagnetic gradient that, in use, provides external magnetomotive controlof magnetic nanoparticles introduced within vasculature of a subject. Inone embodiment, the magnetomotive system comprises a controller that, inuse, causes the robotic arm to manipulate at least one of a position andan orientation of the magnet to create a time-varying magnetic field andto control a direction and a magnitude of a magnetic gradient of themagnet. In one embodiment, the controller is configured to move therobotic arm to position the magnet according to input received from auser. In one embodiment, the magnetomotive system comprises a controlsystem that, in use, provides an interface to the user to allow the userto control the robotic arm.

In accordance with several embodiments, a magnetomotive system forincreasing fluid flow in a circulatory system by wireless manipulationof magnetic nanoparticles is provided. In one embodiment, the systemcomprises a permanent magnet (e.g., cylindrical or octagonal cylindricalmagnet). In one embodiment, the system comprises a first rotationmechanism (e.g., slewing bearing) configured to rotate the magnet abouta first axis of rotation and a second rotation mechanism (e.g., slewingbearing) configured to control a rate of rotation of the magnet about asecond axis (e.g., to provide a time-varying magnetic field). Theslewing bearings can be controlled by worm gears or other controlledmovement mechanisms. In one embodiment, the system comprises a firstmotor (e.g., stepper motor, servo motor) configured to rotate the firstrotation mechanism and a second stepper motor configured to rotate thesecond rotation mechanism. In one embodiment, the system comprises acontroller configured to selectively actuate the first and secondstepper motors. In one embodiment, the direction of the time-varyingmagnetic field is varied with a frequency causing the magneticnanoparticles to travel in a circulating motion. The frequency can be atleast about 0.1 Hz and/or less than or equal to about 100 Hz, includingbut not limited to from about 1 Hz to about 30 Hz, from about 3 Hz toabout 10 Hz, from about 0.5 Hz to about 50 Hz, from about 1 Hz to about6 Hz, from about 0.1 Hz to about 10 Hz, from about 5 Hz to about 20 Hz,from about 10 Hz to about 30 Hz, from about 20 Hz to about 50 Hz, fromabout 40 Hz to about 70 Hz, from about 50 Hz to about 100 Hz,overlapping ranges thereof, about 3 Hz, less than about 5 Hz, less thanabout 10 Hz, less than about 20 Hz, less than about 30 Hz, less thanabout 40 Hz, or less than about 50 Hz.

In accordance with several embodiments, a method is disclosed oftranslating a chemical adjunct into an occluded branch by controllingmagnetic nanoparticles in vasculature of a subject using a magnetomotivesystem. In one embodiment, the method comprises controlling a magnet tomanipulate a magnetic field at a desired location by altering at leastone of a position, a rotation speed, a rotation axis, and a magneticfield strength of the magnet to create a time-varying magnetic field andto control a direction, a magnitude, and a gradient of the time-varyingmagnetic field. In one embodiment, the method comprises manipulating thegradient of the time-varying magnetic field to cause the magneticnanoparticles in the vasculature to accumulate at a targeted location inthe occluded branch. In one embodiment, the method comprises varying thedirection of the time-varying magnetic field to cause the magneticnanoparticles at the targeted location in the occluded branch to travelin a circulating motion in the vasculature. In one embodiment, causingthe magnetic nanoparticles to accumulate and travel in a circulating oroscillating motion at the targeted location increases exposure of anocclusion in the occluded branch to the chemical adjunct. In oneembodiment, the chemical adjunct is a thrombolytic agent.

In accordance with several embodiments, a method is disclosed forcontrolling magnetic nanoparticles using a magnetomotive system. In oneembodiment, the method comprises receiving diagnostic (e.g. imaging,tuning, visually, mechanically, electrically or sonically detecting)data from a diagnostic (e.g., imaging system), such as the SonoSite®M-Turbo™ ultrasound system. In some embodiments, the diagnostic datacomprises information derived from an imaging or detection modalitythat, in use, provides information about vasculature of a subject,relative position of the magnetic nanoparticles, or both. In oneembodiment, the method comprises registering a reference frame of themagnetomotive system to a reference frame of the diagnostic system suchthat the diagnostic data from the diagnostic system is mapped topositions relative to the magnetomotive system. In one embodiment, themethod comprises identifying the magnetic nanoparticles within thediagnostic data from the diagnostic system. In one embodiment, themethod comprises determining a position of the magnetic nanoparticlesrelative to the magnetomotive system. In one embodiment, the methodcomprises planning a navigation path from the position of the magneticnanoparticles to a desired location within the subject based on thediagnostic data from the diagnostic system. In one embodiment, themethod comprises manipulating a magnetic field produced by themagnetomotive system to navigate the magnetic nanoparticles according tothe navigation path. In one embodiment, the method comprises receivinginput from a user, and using the input from the user to manipulate themagnetomotive system. In one embodiment, the method comprisescorrelating a concentration of magnetic particles with an amount ofdiffusion of the thrombolytic agent, and adjusting parameters of atreatment to alter the diffusion of the thrombolytic agent.

In one embodiment, the diagnostic data comprises at least one ofultrasound-based diagnostic (e.g., imaging) data, x-ray data, PET data,MR data, and CT scan data. In one embodiment, registering the referenceframe comprises identifying elements of the diagnostic data, and mappingthe identified elements of the imaging data to positions within thesubject. In one embodiment, registering the reference frame comprisesreceiving diagnostic system information from the diagnostic system, andusing the received diagnostic system information to map the diagnosticdata to positions relative to the magnetomotive system. In oneembodiment, planning the navigation path comprises identifying atherapeutic target using the imaging data, selecting an injection sitefor the magnetic nanoparticles, and designating a route through thevasculature of the subject to arrive at the therapeutic target. In oneembodiment, the magnetic nanoparticles act as contrast agents. In oneembodiment, a mode of operation is selected based on the receiveddiagnostic data. In one embodiment, the mode of operation is at leastone of a collection mode, vortexing mode, and a navigation mode.

These and other features, aspects and advantages of the disclosure willbecome better understood with reference to the following description,examples and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Those of skill in the art will understand that the drawings, describedbelow, are for illustrative purposes only. The drawings are not intendedto limit the scope of the disclosure in any way.

FIGS. 1A and 1B illustrate an example of a permanent-magnet statorsystem whose magnet's North-South pole rotates in a plane parallel tothe system's front face, which is driven by a single motor.

FIG. 2 illustrates a portable positioner cart to which the magnet systemof FIGS. 1A and 1B can be attached.

FIG. 3 illustrates an example of a permanent-magnet stator system whosemagnet's North-South pole rotates in a plane perpendicular to thesystem's front face, which is driven by a single motor.

FIGS. 4A and 4B illustrate an example of a permanent-magnet statorsystem driven by two motors, allowing the magnet to be rotated in anyplane. FIG. 4C illustrates an example of a permanent-magnet statorsystem allowing an angular orientation of the magnet to be controlled.

FIG. 5 illustrates an example of an electromagnet stator system, withpower supplies, attached to an arm positioner.

FIG. 6 illustrates an embodiment of a portable magnetic pod with a railattachment capable of being attached to a bedside rail of a bed orpatient transport unit.

FIGS. 7A to 7C illustrate various embodiments of a user controlinterface for a magnetomotive stator system.

FIG. 8 illustrates an embodiment of a control process.

FIG. 9A illustrates the manipulation of magnetic nanoparticles to createmotion within a blood vessel, in accordance with an embodiment of theinvention.

FIG. 9B illustrates the action of the magnetic field on a magneticnanoparticle to create rotation, in accordance with an embodiment of theinvention.

FIG. 9C illustrates the magnetic manipulation of a magnetic nanoparticledistribution inside a fluid-filled enclosure to create flow patterns, inaccordance with an embodiment of the invention.

FIG. 9D illustrates the magnetic manipulation of a magnetic nanoparticledistribution to amplify the effects of therapeutic agents on a clot, inaccordance with an embodiment of the invention.

FIG. 10 illustrates an embodiment of a method for controlling magneticnanoparticles.

FIG. 11 illustrates the manipulation of a magnet to cross a vesselocclusion, in accordance with an embodiment of the invention.

FIGS. 12A and 12B illustrate an example method of use of a magnetomotivestator system and magnetic nanoparticles for the treatment of a vascularocclusion in the brain, in accordance with an embodiment of theinvention.

FIGS. 13A-13E illustrate a model for the enhanced diffusion oftherapeutic drugs in an area of complete blockage having no fluid flow,in accordance with an embodiment of the invention, where (A) shows avessel having no drug, (B) shows the addition of a drug to the system(shown in grey), but the inability to mix at the site of the blockage,(C) shows the addition of magnetic nanoparticles to the system that aredrawn to the blockage site via a magnet (not shown), (D) showsturbulence created by applying the magnetic field and gradient in atime-dependent fashion and mixing the drug to come closer to contactingthe blockage site, and (E) showing completed diffusion of the drug andcontact at the blockage site via mixing using the magneticnanoparticles.

FIG. 14 illustrates an embodiment of a magnetomotive stator system.

FIG. 15 illustrates an embodiment of an electromagnet magnetomotivestator system surrounding a leg of a patient.

FIG. 16A is a cross sectional drawing displaying a representativetargeted region of a blocked lumen with no flow, under conventionaltreatment.

FIG. 16B is a cross sectional drawing of a targeted region having bloodflow, but with ineffective drug clearance using standard drug delivery.

FIGS. 17A-170 illustrate arranged structuring of magnetic nanoparticlesto create rods as used in procedures according to some embodiments,where (A) shows unorganized nanoparticles in zero field, (B) shows asmall field applied to the nanoparticles and organization into “rods,”and (C) shows a larger field applied to the nanoparticles.

FIGS. 18A-18E illustrate agglomeration of magnetic nanoparticles intorods and depiction of flow generation from the motion of the rodsresulting from an applied magnetic field. FIG. 18A is a plot ofnanoparticle agglomerate rod length as a function of the appliedmagnetic field, showing a limiting length, in accordance with anembodiment of the invention. FIG. 18B illustrates a sequence showingagglomeration of magnetic nanoparticles into a rod under the influenceof an applied magnetic field. FIG. 18C illustrates a rod rotating andtranslating as a result of a time-varying magnetic field. FIG. 18Dillustrates a rod rotating and translating across a surface as a resultof a time-varying magnetic field. FIG. 18E illustrates flow patternsarising from the rotation and translation of one or more rods.

FIGS. 19A-19H illustrate a sequence of end over end motions leading totranslation of magnetic rods formed from a plurality of magneticnanoparticles, in accordance with an embodiment of the invention.

FIGS. 20A and 20B illustrate a characteristic saturation ofnanoparticles with increased density as a result of rotating motionleading to a buildup of magnetic nanoparticles.

FIGS. 21A and 21B illustrate a derivation of the physics of elements andfields leading to magnetic torque on a nanoparticle rod, in accordancewith an embodiment of the invention.

FIG. 21C illustrates the distribution of kinetic energy as a function offrequency of rotation of the rods, in accordance with an embodiment ofthe invention.

FIG. 22A illustrates the introduction of turbulence with spinning rodsin a vessel with no flow, to treat the occlusion problem shown in FIG.16A, in accordance with an embodiment of the invention.

FIG. 22B exhibits motion and effect of drug delivery according to someembodiments for introduction of turbulence in the occluded flow categoryshown in FIG. 16B, in accordance with an embodiment of the invention.

FIG. 23A is a cross section view of a group of rotating rods in agenerally circular motion against a total occlusion in a vessel, inaccordance with an embodiment of the invention.

FIG. 23B is a cross section view of the rotation of rods starting toform a ball, in accordance with an embodiment of the invention.

FIG. 23C is a cross section view of the rotating ball of rods and clotmaterial having opened the obstructed vessel, in accordance with anembodiment of the invention.

FIG. 23D is a cross section view of the ball of FIG. 23C being removedby a small magnet on a guide wire, in accordance with an embodiment ofthe invention.

FIG. 24 is a cross section view of a vessel with rotating magneticcarriers applying therapeutic agents to safely remove occluding materialon a valve leaflet in a blood vessel, in accordance with an embodimentof the invention.

FIG. 25 illustrates the result of end over end motion of a magnetic rod“walk” along a path to a distant clot in a complex vessel, in accordancewith an embodiment of the invention.

FIGS. 26A and 26B illustrate the generation of motion of amagnetically-enabled thrombectomy device which is depicted as a sphere,where (A) shows no field or gradient applied and (B) shows a field andgradient applied causing the sphere to move laterally, in accordancewith an embodiment of the invention.

FIGS. 27A-27D illustrate the use of a rotating magnetically-enabledthrombectomy sphere to address an occluded vessel, in accordance with anembodiment of the invention. FIG. 27A is a cross section view of arotating magnetically-enabled thrombectomy sphere in circular motionagainst a total occlusion in a vessel. FIG. 27B is a cross section viewof the magnetically-enabled thrombectomy sphere wearing away the surfaceof the occlusion. FIG. 27C is a cross section view of themagnetically-enabled thrombectomy sphere having opened the obstructedvessel. FIG. 27D is a cross section view of the magnetically-enabledthrombectomy sphere being removed by a small magnet on a guide wire.

FIG. 28A is a cross section view illustrating a tetheredmagnetically-enabled thrombectomy sphere having opened an obstructedvessel, in accordance with an embodiment of the invention.

FIG. 28B illustrates an embodiment of a tethered magnetically-enabledthrombectomy sphere in which the tether runs through the magneticsphere's rotational axis.

FIG. 28C is another example tether embodiment which loops around themagnet's rotational axis, in accordance with an embodiment of theinvention.

FIG. 29 is a cross section view of a rotating magnetically-enabledthrombectomy sphere in circular motion against plaque on vessel walls,in accordance with an embodiment of the invention.

FIG. 30A illustrates the result of end over end motion of a magnetic rodor magnetic ball “walk” along a path to a distant clot in a complexvessel as imaged by an imaging technology, in accordance with anembodiment of the invention.

FIG. 30B illustrates the ability to recreate the path based on themeasurements made in FIG. 30A.

FIG. 31 illustrates an embodiment of an infusion system havingmicro-bore tubing.

FIGS. 32A and 32B illustrate embodiments of infusion systems havingultrasonic transducers to maintain dispersion of an infusate.

FIG. 33 illustrates an embodiment of an infusion system employingmagnetic energy to maintain dispersion of an infusate.

FIG. 34 illustrates an embodiment of an infusion system having amechanical agitation system configured to maintain dispersion of aninfusate.

FIG. 35 illustrates an embodiment of an infusion system employingmultiple bolus cartridges.

FIGS. 36A and 36B illustrate an embodiment of an infusion systememploying fluid dynamic mixing to maintain dispersion of an infusate.

FIGS. 37A and 37B illustrate the clearance of a thrombosis in the veinof a rabbit using embodiments of the magnetomotive stator system andmagnetic nanoparticles.

FIG. 38 illustrates the dosage response curve of tPA using embodimentsof the magnetomotive stator system showing both reduced time to increaseblood flow in a rabbit, and reduced amount of tPA required to producethe same result, in accordance with an embodiment of the invention.

FIG. 39 illustrates results of testing showing that concentrating a drugusing magnetic nanoparticles is faster than diffusion alone.

FIG. 40 illustrates a graph of blood flow as a function of time for anexample of magnetic nanoparticle-accelerated clot lysis.

FIGS. 41A-41F illustrate an example of bifurcated nanoparticle controlusing a parent vessel.

FIGS. 42A-42D illustrate an example of lysis of biological thrombususing streptokinase and magnetic nanoparticles.

FIG. 43 illustrates graphs of streptokinase and tPA dose responseimprovements.

FIG. 44 illustrates an example test tube setup having defined tPA doseand relative magnetic nanoparticle dose.

FIG. 45 illustrates a graph of lysis rate as a function of relativemagnetic nanoparticle dose.

FIGS. 46A-46G illustrate an example user interface for use in treating apatient with magnetic nanoparticles and a magnetomotive system.

FIGS. 47A and 47B illustrate an embodiment of a magnetic control systemand the positioning of a magnet pod of the magnetic control system withreference to a patient being treated for potential obstruction orblockage in a brain vessel.

FIGS. 48A and 48B schematically illustrate an embodiment of the effectof using the magnetic nanoparticles and magnetic control systemsdescribed herein.

DETAILED DESCRIPTION Abbreviations and Definitions

The scientific and technical terms used in connection with thedisclosure shall have their ordinary meanings (e.g., as commonlyunderstood by those of ordinary skill in the art) in addition to anydefinitions included herein. Further, unless otherwise required bycontext, singular terms shall include pluralities and plural terms shallinclude the singular. The disclosures of The McGraw-Hill Dictionary ofChemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)) andFerrohydro-Dynamics (R. E. Rosensweig, Dover Publications, New York,(1985)) are hereby expressly incorporated by reference herein.

“Patient” shall be given its ordinary meaning and shall include, withoutlimitation, human and veterinary subjects.

“Thrombolytic drug” shall be given its ordinary meaning and shallinclude, without limitation, drugs capable of degrading a blood clot orarteriosclerotic plaque. For example, a thrombolytic drug can includetissue plasminogen activator (tPA), plasminogen, streptokinase,urokinase, recombinant tissue plasminogen activators (rtPA), alteplase,reteplase, tenecteplase, statins, and other drugs, and can include thesedrugs administered alone or co-administered with warfarin and/orheparin.

“Magnetic nanoparticle” shall be given its ordinary meaning and shallinclude without limitation a coated or uncoated metal particle having adiameter greater than or equal to about 1 nm and/or less than or equalto about 1000 nm, greater than or equal to about 10 nm and/or less thanor equal to about 200 nm, greater than or equal to about 15 nm and/orless than or equal to about 150 nm, greater than or equal to about 20 nmand/or less than or equal to about 60 nm, 80 nm, 100 nm, and all integervalues between 1 nm and 1000 nm, e.g., 1, 2, 3, 4, 5, . . . 997, 998,999, and 1000. The appropriate sizes of magnetic nanoparticles candepend on the therapeutic target of the system (e.g., very small vesselscan accept smaller nanoparticles and larger parts of a circulatorysystem can accept larger nanoparticles). Examples of such magneticnanoparticles include superparamagnetic iron oxide nanoparticles. Thenanoparticles may be made of magnetite or other ferromagnetic mineral oriron oxide and, in some embodiments, can be coated with any one or acombination of the following materials: (1) coatings which enhance thebehavior of the nanoparticles in blood by making them either hydrophilicor hydrophobic; (2) coatings which buffer the nanoparticles and whichoptimize the magnetic interaction and behavior of the magneticnanoparticles; (3) contrast agent or agents which allow visualizationwith magnetic resonance imaging, X-ray, Positron Emission Tomography(PET), ultrasound, or other imaging technologies; (4) therapeutic agentswhich accelerate destruction of a circulatory system blockage; (5) stemcells; and (6) thrombolytic drugs. Examples of both coated and uncoatedmagnetic nanoparticles and methods of making such magnetic nanoparticlescan include, for example, those described in U.S. Pat. Nos. 5,543,158,5,665,277, 7,052,777, 7,329,638, 7,459,145, and 7,524,630, the entiredisclosure of each of which is hereby expressly incorporated byreference herein. See also Gupta et al., Biomaterials, Volume 26, Issue18, June 2005, Pages 3995-4021, the disclosure of which is herebyexpressly incorporated by reference herein.

“Fluid obstruction” shall be given its ordinary meaning and shallinclude without limitation a blockage, either partial or complete, thatimpedes the normal flow of fluid through a circulatory system, includingthe venous system, arterial system, central nervous system, andlymphatic system. “Vascular occlusions” are fluid obstructions thatinclude, but are not limited to, atherosclerotic plaques, fatty buildup,arterial stenosis, restenosis, atherosclerosis, arterial thrombi, veinthrombi, cerebral thrombi, embolisms (e.g., pulmonary embolisms),arteriovenous malformations, hemorrhages, other blood clots, and verysmall vessels. Sometimes, fluid obstructions are generally referred toherein as “clots.”

“Substantially clear” shall be given its ordinary meaning and shallinclude without limitation removal of all or part of a fluid obstructionthat results in increased flow of fluid through the circulatory system.For example, substantially clearing the vein includes creating a pathwaythrough or around a thrombus that blocks a blood vessel so that bloodcan flow through or around the thrombus.

“Very small vessel” shall be given its ordinary meaning and shallinclude without limitation a circulatory system fluid pathway having adiameter from about 1 μm to about 10 μm.

“Increased fluid flow” shall be given its ordinary meaning and shallinclude without limitation increasing the throughput of a blockedcirculatory system from zero to something greater than zero. Forexample, in flowing circulatory systems, the term increased fluid flowcan mean increasing the throughput from a level prior to administrationof one or more magnetic nanoparticles in a patient to a level greaterthan the original fluid flow level.

“Agglomerate” shall be given its ordinary meaning and shall includewithout limitation rotational clustering and chaining of a group ofindividual magnetic rotors in a manner to develop “rods” from themagnetic nanoparticles (for example, as described herein with respect toFIG. 17). Such a group of rotating rotors forms an ensemble in whichindividual rotors generally rotate simultaneously and travel in the samedirection as a group. The application of the combined magnetic field andgradient over time is the manner of assembling the rods. Such a groupcomprises characteristics that can different than what can be expectedof individual rotors acting alone and can create hydrodynamic forces ina fluid stream or still fluid to create turbulence or enhance thediffusion of a composition or liquid in the fluid stream or still fluid.

“Treatment” shall be given its ordinary meaning and shall includewithout limitation an approach for obtaining beneficial or desiredclinical results. For purposes of this disclosure, beneficial or desiredclinical results include, but are not limited to, one or more of thefollowing: improvement or alleviation of any aspect of fluid obstructionin the circulatory system including, but not limited to, fluidobstructions (e.g., stroke, deep vein thrombosis), coronary arterydisease, intracranial artery stenosis, ischemic heart disease,atherosclerosis, cardiovascular diseases, and high blood pressure.

“Drug, compound, or pharmaceutical composition” shall be given theirordinary meanings and shall include without limitation a chemicalcompound or composition capable of inducing a desired therapeutic effectwhen properly administered to a patient, for example enzymaticdegradation of a thrombus or atherosclerotic plaque.

“Effective amount” shall be given its ordinary meaning and shall includewithout limitation an amount of a therapeutic agent (e.g., drug,chemical adjunct, compound or pharmaceutical composition) sufficient toeffect beneficial or desired results including clinical results such asalleviation or reduction in circulatory system fluid blockage. Aneffective amount can be administered in one or more administrations. Forexample, an effective amount of drug, compound, or pharmaceuticalcomposition can be an amount sufficient to treat (which includes toameliorate, reduce incidence of, delay and/or prevent) fluid blockage inthe circulatory system, including vascular occlusions in the head andextremities. The effective amount of a therapeutic agent can includecoated or uncoated magnetic nanoparticles formulated to be administeredto a patient. The effective amount may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable result may be or is achieved.

“Reducing incidence” shall be given its ordinary meaning and shallinclude without limitation any of reducing severity (which can includereducing need for and/or amount of (e.g., exposure to) drugs and/ortherapies generally used for these conditions, including, for example,tPA), duration, and/or frequency (including, for example, delaying orincreasing time to displaying symptoms of circulatory system blockage).For example, individuals may vary in terms of their response totreatment, and, as such, for example, a method of reducing incidence offluid blockage in a patient reflects administering the effective amountof the magnetic nanoparticles, whether or not in combination with atherapeutic agent, based on a reasonable expectation that suchadministration may likely cause such a reduction in incidence in thatparticular individual.

“Ameliorating” one or more symptoms of circulatory system blockage shallbe given its ordinary meaning and shall include without limitation alessening or improvement of one or more symptoms of circulatory systemblockage as compared to not administering a magnetic nanoparticle,whether or not in combination with a therapeutic agent, using the systemdescribed herein. Ameliorating can also include shortening or reducingin duration a symptom.

“Delaying” the development of a symptom related to circulatory systemblockage shall be given its ordinary meaning and shall include withoutlimitation to defer, hinder, slow, retard, stabilize, and/or postponeprogression of the related symptoms. This delay can be of varyinglengths of time, depending on the history of the disease and/orindividuals being treated. For example, a sufficient or significantdelay can, in effect, encompass prevention in that the individual doesnot develop symptoms associated with circulatory system blockage. Amethod that delays development of the symptom is a method that reducesprobability of developing the symptom in a given time frame and/orreduces extent of the symptoms in a given time frame, when compared tonot using the method. Such comparisons may be based on clinical studies,using a statistically significant number of subjects.

“Pharmaceutically acceptable carrier” shall be given its ordinarymeaning and shall include without limitation any material which, whencombined with a magnetic nanoparticle and/or an active ingredient, isnon-reactive with the subject's immune system and allows the activeingredient to retain biological activity. For example, pharmaceuticallyacceptable carriers include pharmaceutical carriers such as a phosphatebuffered saline solution, water, emulsions such as oil/water emulsion,and various types of wetting agents. Examples of diluents for parenteraladministration are phosphate buffered saline or normal (0.9%) saline.

“Pharmaceutically acceptable” shall be given its ordinary meaning andshall include without limitation being approved by a regulatory agencyof the Federal or a state government or listed in the U.S.Pharmacopoeia, other generally recognized pharmacopoeia in addition toother formulations that are safe for use in animals, and moreparticularly in humans and/or non-human mammals.

Overview of Magnetomotive Stator System and Methods for Wireless Controlof Magnetic Rotors

Systems and methods are described for the physical manipulation of freemagnetic rotors using a remotely placed magnetic field-generating statoraccording to several embodiments. Some embodiments of the inventionrelate to the control of magnetic nanoparticles to increase contact of atherapeutic target in a circulatory system with a therapeutic agent(e.g., a pharmaceutical compound, a thrombolytic drug), which can resultin increased fluid flow and the substantial clearance of fluid blockagesof the circulatory system. In various embodiments, the system enhancesdiffusion of the therapeutic agent and uses permanent magnet-based orelectromagnetic field-generating stator sources. Magnetic fields andgradients can be used to act on magnetic nanoparticle agglomerates(e.g., nanoparticle rods, spheres or rotors) and/or magneticthrombectomy devices to reduce circulatory system blockages, includingvascular occlusions, in a patient.

In various embodiments, the system and methods described herein can beused to treat fluid blockages of the circulatory system in the head(e.g., the brain) and in the extremities of the body, such as thevasculature of arms and legs. The systems and methods herein can also beused to facilitate treatment of therapeutic targets in the nervoussystem (e.g., delivered into cerebrospinal fluid) and lymphatic system(e.g., lymph nodes). In some embodiments, the systems and methodsdescribed herein can be used to transport therapeutic agents (e.g.,drugs, antibodies or other molecules) across the blood-brain barrier. Insome embodiments, the systems and methods described herein can be usedto deliver genes or stem cells. In some embodiments, the systems andmethods described herein can be used to facilitate treatment of tumorsor cancerous tissues in various oncology applications. Benign masses canalso be treated. In one embodiment, the delivery of lytic agents totissue masses is facilitated via the magnetic particles disclosedherein.

Some embodiments of the invention provide for a magnetically producedscouring process generated by magnetic nanoparticles and/ormagnetically-enabled thrombectomy devices acting on fluid blockage incombination with the mechanically-enhanced dissolving or lytic processof the therapeutic agent (e.g., thrombolytic agent) that is used. Inaccordance with several embodiments, the magnetic actions are derivedfrom a rotating magnetic field from an external magnet source which alsoprovides a pulling magnetic gradient that is not rotating. This externalcontrol may advantageously provide forces and actions on circulatorysystem blockages generally without mechanical invasion of the location.In accordance with several embodiments, the systems and methodsdescribed herein can greatly increase interaction of the therapeuticagent with the target circulatory system blockage. The interaction mayleave residue that can be collected magnetically in such a way as toleave venous walls or valves undamaged in the process. Another featureof the systems and methods described herein, in some embodiments, is theability to use drug and stirring conditions so that substantially all ofthe residue that is removed forms a small soft clump with the magneticnanoparticles that can be captured by a tiny magnet on the tip of aguide wire. In one embodiment, to achieve these features, the system canuse a rotating magnetic field in combination with a directed magneticgradient to act on magnetic nanoparticles or magnetically-enabled fluidblockage clearing devices.

In some embodiments, the rotating magnetic field is generated bymechanically rotating a strong permanent magnet having an orientationthat rotates the field at the target site, and at the same time presentsa steady magnetic gradient in a desired direction. In some embodiments,two or more magnetic coils can be used with appropriate phasing toprovide rotating fields with a gradient. When three or more coils areused, at least two coils can have axes having some perpendicularcomponent to each other to provide additional magnetic spatial andtiming features. For instance, two coils can have perpendicular axes andone can employ current lagging the other by 90 degrees to create arotating field at the target position. A third coil can be located andoriented to provide appropriate gradients at the target site, as well asindependent functions such as modulation.

With electronic control of the currents, a wide array of fields andgradients can be applied with a large number of time-related events. Inone embodiment, the application of a rotating field with a gradient to aslurry of magnetic nanoparticles can provide a defined type ofarrangement of the grouping: that is the “agglomeration” of magneticnanoparticles that cause them to form aligned rods of approximately 2 mmin length or less.

For example, a field of about 0.02 Tesla at the target site, incombination with a gradient of about 0.4 Tesla/meter, can create anagglomeration of magnetic nanoparticles (e.g., separated nanoparticlerods of length varying approximately from one to two millimeters inlength). These agglomerates can remain largely intact in vitro and invivo, but can be sufficiently flexible to provide “soft brushing” whenrotated. It has been observed that on rotation the nanoparticle rods can“walk” along a surface in a vessel, and when in contact with a fluidblockage, such as a blood clot, can remove minute particles of the clotmaterial with the aid of the thrombolytic drug. The nanoparticle rodscan softly “scrub” off fractions of the clot material continuously, insome cases without residue components of significant size. In othercases, depending on the type and location of obstruction, the deliveryof therapeutic agents (e.g., thrombolytic drugs) can be timed so thatthe residue ends up in a soft small magnetic ball, which can be capturedmagnetically and removed. In some embodiments, contact of thenanoparticle rods with the blood clot or other fluid obstruction isincidental and not required to facilitate removal or degradation of theclot or fluid obstruction.

Ultrasound and other imaging technologies (e.g., radiography, magneticresonance, nuclear medicine, photo acoustic, thermography, tomography)can be used to visualize the progress of treatment. For example,transcranial ultrasound imaging could be used to confirm clotdestruction visually in a cranial embolism or stroke. Contrast agentsand other agents that enhance visualization of the magneticnanoparticles can also be used (e.g., iodine, barium, gadolinium). Theimaging technologies can transmit images to a display device to providean operator real-time feedback so that the operator can navigate orotherwise control movement of the magnetic nanoparticles.

In several embodiments, using a rotating magnetic field and gradientapparatus, fields of 0.02 Tesla with gradients of 0.4 Tesla/meter at thetarget site facilitate more precise control over the rotation of a smallmagnetic ball approximately 1.5 mm in diameter. In one embodiment,proper alignment of the magnetic gradient, the ball-like structure canbe made to navigate the vessels and increase drug mixing at theblockage. In a similar manner, coatings that comprise thrombolyticagents and/or surface features can be added to enhance destruction of ablockage.

The numerical parameters used can vary, depending on the particularnature of the circulatory system blockage, the thrombolytic drug, and/orthe design of the magnetically-enabled thrombectomy devices ornanoparticle rods. Rotational frequencies (e.g., greater than or equalto 0.1 Hz and/or less than or equal to 100 Hz, including but not limitedto from about 1 Hz to about 30 Hz, from about 3 Hz to about 10 Hz, fromabout 0.5 Hz to about 50 Hz, from about 1 Hz to about 6 Hz, from about0.1 Hz to about 10 Hz, from about 5 Hz to about 20 Hz, from about 10 Hzto about 30 Hz, from about 20 Hz to about 50 Hz, from about 40 Hz toabout 70 Hz, from about 50 Hz to about 100 Hz, overlapping rangesthereof, less than 5 Hz, less than 10 Hz, less than 20 Hz, less than 30Hz, less than 40 Hz, less than 50 Hz) can be effective with a range ofmagnetic field magnitudes that can be generated by magnets (e.g.,greater than or equal to 0.01 Tesla and/or less than 1 Tesla, includingbut not limited to from about 0.01 Tesla to about 0.1 Tesla, from about0.05 Tesla to about 0.5 Tesla, from about 0.1 Tesla to about 0.6 Tesla,from about 0.3 Tesla to about 0.9 Tesla, from about 0.5 Tesla to about 1Tesla, overlapping ranges thereof, less than 1 Tesla, less than 0.5Tesla, less than 0.25 Tesla, less than 0.1 Tesla), all in a volume ofabout one cubic foot, or by coils with somewhat larger volume. Gradientstrength can be greater than or equal to 0.01 Tesla/m and/or less thanor equal to 10 Tesla/m, including but not limited to from about 0.01Tesla/m to about 1 Tesla/m, from about 0.01 Tesla/m to about 3 Tesla/m,from about 0.05 Tesla/m to about 5 Tesla/m, from about 1 Tesla/m toabout 4 Tesla/m, overlapping ranges thereof, less than 5 Tesla/m, lessthan 3 Tesla/m, less than 2 Tesla/m, less than 1 Tesla/m). The gradientdirection generally centers on the center of mass for a permanentmagnet, and using an electromagnet can center on one of the coils, andin combination, can center between one or more coils.

Fluid Blockages of the Circulatory System

Parts of the body where fluid blockages of the circulatory system occurinclude the blood vessels associated with the legs and the brain. Twomajor hydrodynamic properties of such blockage are observed in thevasculature: low blood flow (e.g., <1 cm/sec) or total blockage. Ineither case, existing modes of delivery of drugs for dissolvingocclusions at surfaces or mechanical removal of, for example, thrombusmaterial cannot effectively clear a degraded and impeding layer on aclot surface to be removed to allow fresh drug interaction with anunderlayer. This can result in dangerous components moving downstream,which can result in a more dangerous blockage or death. In a typicalflow situation, there are locations where the flow does not effectivelypenetrate or target the intended site. In other situations, it is notpossible to navigate a thrombectomy device to the target due tosmallness (e.g., a very small vessel) or complexity of thethree-dimensional shape of the occluded vessel.

Different thrombolytic drugs can be used in the thrombolytic process.For example, streptokinase can be used in some cases of myocardialinfarction and pulmonary embolism. Urokinase or alteplase can be used intreating severe or massive deep venous thrombosis, pulmonary embolism,myocardial infarction and occluded intravenous or dialysis cannulas.Tissue Plasminogen Activator (“tPA” or “PLAT”) can be used clinically totreat stroke. Reteplase can be used to treat heart attacks by breakingup the occlusions that cause them. Anticoagulants (e.g. heparin,fondaparinux, dextran, ardeparin, danaparoid) may also be used to treatpulmonary embolism, deep venous thrombosis, or other fluid obstructions

In the case of stroke (e.g., cardioembolic stroke or acute ischemicstroke), tPA is used successfully in many cases, but in many cases theeffect of the drug is to leave downstream residue in clumps large enoughto cause further blockage and sometimes death. In addition, the normalthrombolytic dosage administered to patients is related to increasedbleeding in the brain. In many cases, the effectiveness of chemicalinteraction of the thrombolytic agent with the blockage is slow andinefficient (or the thrombolytic agent or other agent cannot even reachthe blockage due to low or no flow), leaving incomplete removal of theblockage. In blockages in the extremities, mechanical means of stirringand guiding the drug are limited, often difficult, and can be dangerous.In many cases, venous valves in the region of the procedure are damagedor not made blockage-free in procedures currently used. Some embodimentsdescribed herein advantageously provide new systems and methods forsignificant improvements in dealing with these major obstacles intreating occlusions of the blood flow.

Treatment of stroke using the magnetic nanoparticles and magnetomotivesystems described herein can advantageously result in a recanalizationefficacy that is comparable to highly effective thrombectomy devices,but the systems described herein can be deployed earlier and withoutcausing physical trauma to vasculature. Earlier deployment can result infavorable results, such as earlier reperfusion of the brain, andconsequently better outcomes compared to treatments using IV-tPA,interventional devices, or a combination of the two. In severalembodiments, treatment is administered within a prescribed time periodafter onset of stroke (e.g., within 2-4 hours after onset of stroke). Insome embodiments, treatment is effective even outside of a target orcritical time period after onset of stroke (e.g., outside of a 3-houronset-to-therapy initiation window). Earlier recanalization can behighly predictive of an improved neurological outcome.

In several embodiments, use of the systems, magnetic nanoparticles, andmethods described herein can result in complete recanalization (e.g.,complete lysis of a clot) less than one hour after initiation oftreatment, with signs, symptoms, or evidence of recanalization orreperfusion being manifest as early as within ten minutes afterinitiation of treatment (less than ten minutes, less than 20 minutes,less than 30 minutes, less than 45 minutes, less than 50 minutes).Evidence of recanalization can be determined by decreases in NIH StokeScale (NIHSS) scores. For example, improvement in NIHSS scores after tenminutes of initiating treatment may be double what they typically arefor thrombolytic agent treatment (e.g., IV-tPA) alone (e.g., 8-10 pointimprovement instead of 4 point improvement, on average). NIHSS scoresprovide a quantitative measure of stroke-related neurologic deficit andthe scores are used to evaluate the effect of acute cerebral infarctionon the levels of consciousness, language, neglect, visual-field loss,extraocular movement, motor strength, ataxia, dysarthria, and sensoryloss. In accordance with several embodiments, treatment using thesystems and methods described herein results in an improvement ofbetween 8 to 15-points in NIHSS scores at 1 hour after treatment and/orat 24 hours after treatment.

Magnetomotive Stator System

In accordance with several embodiments, a therapeutic system is providedcomprising a magnet having a magnetic field and a gradient forcontrolling movement of magnetic rotors (e.g., magnetic nanoparticleagglomerates, spheres or rods) in vasculature of a circulatory systemand a controller for positioning and rotating the field and the gradientin a manner to agglomerate and/or traverse the magnetic rotors withrespect to a therapeutic target (e.g., clot or other fluid obstruction)in the circulatory system. Using the therapeutic system, contact of thetherapeutic target with a pharmaceutical composition in the circulatorysystem can be increased. In various embodiments, the pharmaceuticalcomposition is attached or coupled to the magnetic rotor, and, in otherembodiments, is administered to the circulatory system separate from themagnetic rotors. In certain embodiments, the pharmaceutical compositionis a thrombolytic drug (e.g., tPA, alteplase, streptokinase, urokinase,reteplase, or combinations thereof).

Therapeutic targets of the system can include fluid obstructions suchas, but not limited to, atherosclerotic plaques, fibrous caps, fattybuildup, coronary occlusions, arterial stenosis, arterial restenosis,vein thrombi (e.g., deep vein thrombosis), arterial thrombi, cerebralthrombi, embolism (e.g. pulmonary embolism), hemorrhage, very smallvessels, blood clots in the eye, vascular tumors (e.g., hemangioma,lymphangioma, hemangioendothelioma, Kaposi sarcoma, angiosarcoma,hemangioblastoma), arteriovenous malformations in the arteries or veinsof the brain or other organs (e.g., true arteriovenous malformations,occult or cryptic or cavernous malformations, venous malformations,hemangioma, dural fistulas), other fluid obstructions, or anycombination of these. Therapeutic or diagnostic targets of the systemcan also include any organ or tissue of the body (e.g., heart, brain,legs, arms, lungs, vestibular system, tumors or cancerous tissue) or thevascular associated with the organ or tissue). For example, therapeuticor diagnostic targets can be targets identified for stem cell or genetherapy (e.g., gene delivery). In some embodiments, the magnetic rotorscan be delivered in conjunction with therapeutic or diagnostic agentswithin spinal fluid (e.g., cerebrospinal fluid). In various embodiments,the circulatory system is vasculature of a subject (e.g., arteries orveins of a human or veterinary patient).

In various embodiments, the therapeutic system comprises a permanentmagnet coupled to a motor, and the controller controls a motor toposition the magnet at an effective distance and an effective plane withrespect to the therapeutic target, and rotates the magnet at aneffective frequency with respect to the therapeutic target. In variousembodiments, the therapeutic system comprises an electromagnet having amagnetic field strength and magnetic field polarization driven byelectrical current, and the controller positions the electromagnet at aneffective distance and an effective plane with respect to thetherapeutic target, and rotates the magnetic field of the electromagnetby adjusting the electrical current.

The therapeutic system can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, such that a user can control themagnetic rotors to clear the therapeutic target at least in part byadjusting a frequency of the rotating magnetic field, a plane of therotating magnetic field with respect to the therapeutic target, and/or adistance of the rotating magnetic field with respect to the therapeutictarget. In various embodiments, the therapeutic target can be athrombosis in a human blood vessel. In various embodiments, the magneticrotors can be magnetic nanoparticles injected into the circulatorysystem.

In various embodiments, the obstruction to be treated using the systemis a thrombosis in a human blood vessel, and the magnetic rotors areformed by magnetic nanoparticles injected into the circulatory system.In the system, according to one embodiment, the magnetic rotors traversethrough the fluid in a generally circular motion by repeatedly (a)walking end over end along the blood vessel away from the magnetic fieldin response to the rotation of the rotors and an attractive force of themagnetic field, and (b) flowing back through the fluid towards themagnetic field in response to the rotation of the rotors and theattractive force of the magnetic field.

In some embodiments, a system is provided for increasing fluid flow in acirculatory system comprising a magnet having a magnetic field forcontrolling magnetic rotors in the fluid, a display for displaying, to auser, the magnetic rotors and the therapeutic target in the fluid, and acontroller, in response to instructions from the user, controlling themagnetic field to: (a) position the magnetic rotors adjacent to thetherapeutic target, (b) adjust an angular orientation of the magneticrotors with respect to the therapeutic target, and/or (c) rotate andtraverse the magnetic rotors through the fluid in a circular motion tomix the fluid and substantially clear the therapeutic target.

In various embodiments, the display can display real time video of themagnetic rotors and the therapeutic target, and the display cansuperimpose a graphic representative of a rotation plane of the magneticfield and another graphic representative of the attractive force of themagnetic field on the real time video. In some embodiments, the magnetcan be a permanent magnet coupled to a motor and a movable arm, and thecontroller can include a remote control device for a user to manipulatethe position, rotation plane and/or rotation frequency of the magneticfield with respect to the therapeutic target.

In some embodiments, the display can adjust the graphics in response toinstructions received from the user through the remote control device.In various embodiments, the magnet can be an electromagnet coupled to amotor and a movable arm, and the controller can perform image processingto identify the location, shape, thickness and/or density of thetherapeutic target, and can automatically manipulate the movable arm tocontrol the position, rotation plane and/or rotation frequency of themagnetic field to clear the therapeutic target.

In some embodiments, the magnetic rotors are formed by magneticnanoparticles which combine in the presence of a rotating magneticfield. In some embodiments, the fluid can be a mixture of blood and atherapeutic agent (e.g., a thrombolytic drug), the blood and therapeuticagent being mixed by the generally circular motion of the magneticrotors to erode and substantially clear the therapeutic target. In someembodiments, the generally circular motion of the magnetic rotors canredirect the therapeutic agent from a high flow blood vessel to a lowflow blood vessel which contains the therapeutic target. In someembodiments, a varying magnetic field causes the magnetic rotors toestablish or increase a flow of blood towards the therapeutic target,such as an occluded blood vessel branch, thereby increasing a diffusionand efficacy of the therapeutic agent (e.g., increasing tPA diffusionand accelerating destruction of a clot). In some embodiments, theincreased diffusion and efficacy is caused by combining nanoparticles toform nanoparticle rods having a length between 0.1 and 2 millimeterswhen exposed to a rotating time-varying magnetic field magnitude ofbetween 0.01 Tesla and 0.1 Tesla and a magnetic gradient strength ofbetween 0.01 Tesla/meter and 5 Tesla/meter and wherein the rotationfrequency is between 1 Hz and 10 Hz (e.g., between 1 and 6 Hz, between 2and 5 Hz, between 3 and 7 Hz, between 1 and 3 Hz, between 4 and 8 Hz,between 5 and 10 Hz, or overlapping ranges thereof).

An example embodiment of a magnetomotive stator system is illustrated inFIG. 1A (isometric view) and FIG. 1B (cross-section view). The operationof components is shown for this system involving rotation about a singleaxis 132. The permanent magnet cube 102 possesses a North 104 and aSouth 106 magnetic pole. In one embodiment, the permanent magnet 102measures 3.5 inches on each side. The permanent magnet 102 may comprisea number of permanent magnet materials, including Neodymium-Boron-Ironand Samarium-Cobalt magnetic materials, and may be made much bigger orsmaller. For example, the permanent magnet 102 can be greater than orequal to 1 inch on each side and/or less than 10 inches on each sideincluding but not limited to between about 1 inch and about 5 inches,between about 2 inches and about 6 inches, between about 3 inches andabout 8 inches, between about 3 inches and about 4 inches, between about4 inches and about 10 inches, overlapping ranges thereof, less than 6inches, less than 5 inches, less than 4 inches. The shape of thepermanent magnet 102 can be a shape other than a cube, such as, forexample, a sphere, a cylinder, a rectangular solid, an ellipsoid, orsome other shape. Other configurations of the permanent magneticmaterial may improve performance in shaping the field so that aspects ofthe magnetic field and gradient are improved or optimized in terms ofstrength and direction. In some embodiments, the permanent magneticmaterial may be configured in a way to make the system more compact. Acylinder comprising permanent magnetic material is one such example.Cylindrical magnets may reduce the mass of the magnet and allow the massof the magnet to be positioned closer to the patient. In someembodiments, simple rectangular and cubical geometries may be morecost-effective to purchase or manufacture.

The face of the permanent magnet 102 in which the North 104 and South106 poles reside is glued, attached, bonded, affixed, welded, orotherwise fastened or coupled to a mounting plate 108. The mountingplate 108 can comprise magnetic or nonmagnetic material. Optionally,magnetic materials can be used to strengthen the magnetic field for someconfigurations of the permanent magnetic material. In some embodiments,nonmagnetic mounting plates can be desirable, as they may be easier toaffix or couple to the permanent magnet 102.

In one embodiment, this mounting plate 108 is attached to a flange 110that passes through a first bearing 112 and a second bearing 114, bothof which are supported by the bearing mounting structure 116. Manystandard bearings are at least partially magnetic. Accordingly, in someembodiments, the flange 110 is constructed from a nonmagnetic materialto ensure the magnetic field does not travel efficiently from the flange110 into the bearings 112 and 114. If this were to happen, the bearingscould encounter more friction due to the magnetic attraction of theflange 110 to the bearings 112 and 114.

In one embodiment, the end of the flange 110 is connected to a coupling118, which connects to a drive motor 120. The motor 120 may be a DCmotor or an AC motor. A high degree of precision is capable with a servomotor. In some embodiments, a step-down gearbox may be advantageouslyused to spin the permanent magnet 102 at the desired rotation frequency,given that many motors typically spin faster than is desired for thewireless control of magnetic rotors as described herein.

The drive motor 120 is attached to a motor support structure 122, whichaffixes the drive motor 120 to a platform 124, according to oneembodiment. Attached to the platform 124 is a suspension mountingbracket 126 (located but not shown in FIG. 1B), which is connected to asuspension arm 128. The suspension arm 128 possesses an attachment joint130. The suspension arm 128 may be suspended from overhead, from theside, from the bottom, or from some other location depending on adesirable placement of the magnetomotive stator system.

Operation of the Magnetomotive Stator System

The magnetomotive stator system (e.g., magnetomotive stator system 602of FIG. 7A) can be positioned by the use of a portable support base 202as shown in FIG. 2. Once in place, and as shown in FIG. 7A, a computercontrol panel 604 with a display (e.g., computer display) 606 and usercontrol buttons 608 are used in one embodiment to specify theorientation of the magnetic rotation plane 616 at the user-defined pointin space 610. In some embodiments, the display 606 is a touchscreendisplay. The field and gradient are manipulated in the physical space610. The rotation plane's normal vector 614 can be specified by the userin the global coordinate system 612 at the point in space 610, using thecontrol button 608 or a handheld controller 622. Within the magneticrotation plane 616 is the initial orientation of the magnetic field 618,which may be set automatically by the computer or manually by a user oroperator. The user can specify the direction of the magnetic fieldrotation 620 in the magnetic rotation plane 616.

An embodiment of a control process is illustrated in FIG. 8. One, more,or all of the steps in the control process can be automaticallyperformed by a computing device. One or more of the steps can beperformed by an operator. At block 702, a point in space forthree-dimensional control is identified. At block 704, an orientation ofthe axis of the magnetic field spin, which is perpendicular to themagnetic field, is set. This step can include the specification of therotation plane's normal vector 614. Using a right-handed coordinatesystem, the magnetic field can rotate clockwise around the normal vector614. At block 706, the initial direction of the magnetic field 618 isset. In some embodiments, a computer (e.g., the controller 604) canautomatically set the initial direction of the magnetic field 618. Atblock 708, the frequency of field rotation within the magnetic rotationplane 616 is set by the user or automatically by the computer. Thestrength of the magnetic gradient is calculated at block 710 and thestrength of the magnetic field is calculated at block 712. At block 714,control parameters are calculated for the magnetomotive system. Thecontrol parameters can determine the desired rotating magnetic field andmagnetic gradient. For a permanent magnet system, the control parameterscan correspond to the rotation speed of the drive motor(s) 120. For anelectromagnet system, the control parameters can describe the change incurrent in time. Once the control parameters are calculated, themagnetomotive stator system can be turned on at block 716 and themagnetic field and gradient are applied to a target area. If it isdesired or calculated that the magnetic rotation plane 616 should bechanged at block 718, the control process loops back to block 704.

Assuming the magnetomotive stator system is attached to the portablesupport base 202, the platform 124 may be oriented by the user throughthe suspension mounting brackets 126 attached to the suspension arm 128,which is itself attached to the suspension arm attachment joint 130. Thesuspension arm attachment joint 130 connects to an arm positioner 212connected to the portable support base 202. The suspension armattachment joint 130 allows rotation of the magnetomotive system aboutthe end of the arm positioner 212. The suspension arm attachment joint130 also allows the platform base 124 to be rotated in the planeperpendicular to that allowed by the suspension arm attachment joint130. The motor 120, which is attached to the platform base 124 via themotor support structure 122, spins at a desired frequency. Thisspinning, or rotating, motion is coupled to the mounting flange 110 viathe drive coupling 118. The first bearing 112 and the second bearing 114allow for the mounting flange 110 to rotate smoothly. These bearings areaffixed to the platform 124 via the bearing mounting structure 116. Thespinning, or rotating, flange 110 is rigidly attached to the magnetmounting plate 108, which is attached to the permanent magnet 102. Thus,the motor 120 spin is transmitted to the permanent magnet 102. Thelocation of the North magnetic pole 104 and the South magnetic pole 106at the ends of the permanent magnet 106 results in the desired magneticfield rotation plane 616. In this magnetic field rotation plane 616, themagnetic field rotates parallel to the front face of the magnet for allpoints located on the central drive axis 132.

As an example, for the manipulation of magnetic nanoparticles within thebody, the user-defined point in space 610 may be inside the head 624 forischemic stroke therapies in which magnetite nanoparticles aremanipulated to rapidly and safely destroy clots. Likewise, theuser-defined point in space 610 may be inside the leg 626 for deep-veinthrombosis therapies in which magnetite nanoparticles are manipulated torapidly and safely destroy clots.

As an example of magnetic nanoparticle manipulation in accordance withseveral embodiments, FIG. 9B illustrates a magnetic nanoparticle 802,which possesses a particle North magnetic pole 804 and a particle Southmagnetic pole 806, that is rotated by the clockwise rotatingmagnetomotive-generated magnetic field 812 relative to the particlereference coordinate system 808. The rotating magnetic field 812 causesthe magnetic nanoparticle to spin in the direction of the clockwiserotation angle 810. When a magnetic gradient 814 is applied and asurface 816 is present (e.g., a vessel wall), as illustrated in FIG. 9A,the clockwise rotating magnetomotive-generated magnetic field 812results in traction against the surface 816, resulting in translation818 parallel to the surface (e.g., to the right as shown in FIG. 9A).

In the presence of a fluid 820 contained within an enclosing region 822,as illustrated in FIG. 9C, the manipulation of the magneticnanoparticles when combined with the magnetic gradient 814 results incirculating fluid motion 824 in several embodiments. When used todestroy vessel obstructions 830 within a blood vessel 828, whichcontains blood 826 as illustrated in FIG. 9D, themagnetomotive-generated mixing can result in improved mixing of aclot-busting (thrombolytic) drug within the blood 826. The improvedmixing facilitates increased contact and interaction of the therapeuticagent with the vessel obstructions 830 than would occur if the fluid wasstagnant and not mixed, which advantageously allows for the dose of thethrombolytic drug to be lowered from standard prescribed doses which, byreducing the bleeding associated with higher doses of thrombolyticdrugs, results in a safer procedure. It also speeds the thrombolyticprocess. For example, the magnetic nanoparticles can be manipulated toform a vortex (e.g., predictably circulate) in a region of stagnant flowso that the thrombolytic drug is better mixed, resulting in a moreefficient chemical interaction. Creating a vortex can also draw in moreof the thrombolytic drug near the region of turbulent flow.

Real-Time Control with Diagnostic Imaging or Detection

In some embodiments, the system provides real-time information forimproved control of the magnetic nanoparticles. The magneticnanoparticles can be configured to be detectable with an imagingmodality. For example, the magnetic nanoparticles may be attached to acontrast or nuclear agent to be visible using an x-ray-based system orPET scanner, respectively. Other imaging modalities can include nuclearmagnetic resonance spectroscopy, magnetic resonance imaging, computedtomography, and/or Doppler (e.g., transcranial Doppler) which may detectthe fluidic current created by the magnetic nanoparticles.Ultrasound-based diagnostic and/or imaging modalities may also be used.For example, in some embodiments, an external ultrasound-baseddiagnostic system (e.g., Doppler ultrasound system) may be tuned to therotation frequency of the rotating nanoparticle rotors or rods formed bythe magnetic nanoparticles (e.g., 3 Hz) to identify or detect thelocation of the nanoparticle rotors or rods, thereby providing anindication of a location of a fluid obstruction or other therapeutictarget and/or progress of recanalization or other treatment. Thedetection of the location of the rotating nanoparticle rotors or rodscan provide a useful indication as to whether circulation is occurring(or whether recanalization has been achieved) without requiring a CTangiography or an MRI). In some embodiments, the ultrasound-baseddiagnostic system provides continuous, real-time monitoring of bloodflow. Other technologies or modalities capable of tuning to rotationalfrequencies may also be used.

Combining the control system with an optional diagnostic (e.g., imagingor detection) system advantageously provides the ability to improvedirected therapy in some embodiments. In some implementations, thediagnostic system can provide information suitable for tracking theinfusion of a therapeutic agent (e.g., chemical adjunct) in real-timetoward therapeutic targets (e.g., low-blood-flow lumens having one ormore partial or complete obstructions or blockages). For example,magnetic nanoparticles can be configured to act as contrast agents inapplications where magnetic nanoparticles are associated with one ormore drugs or therapeutic agents. Using magnetic nanoparticles in suchapplications allows the nanoparticles to be used as a measure of drugdiffusion. Based on imaging or other diagnostic data, the control systemcan correlate a concentration of the contrast agent with an amount ofmagnetic nanoparticles at a location. As a result, parameters of thetherapy can be adjusted to alter diffusion of the drug or therapeuticagent (e.g., by altering the manipulation of the magnetic nanoparticlesby adjusting the control parameters of the magnetic-based controlsystem).

In certain embodiments, the diagnostic system can provide information tothe system and/or a user suitable for switching the system betweenoperational modes. For example, the imaging system can provide images orother input to the control system indicating the location andconcentration of magnetic nanoparticles within a subject. Based on thisinformation, the system or a user can cause the magnetic system toprovide magnetic fields configured to collect magnetic nanoparticles ina defined location or cause the magnetic system to provide magneticfields configured to mix or vortex magnetic nanoparticles in a location.By manipulating the magnetic system according to received imageinformation, the control system can control the infusion of magneticnanoparticles in response to conditions within the subject and in one,two, or three dimensions, thereby improving the ability to direct thetherapy.

The imaging modality can be any imaging modality capable of resolving adevice or chemical agent which is affected by the fluidic currentgenerated by the magnetic nanoparticles. The modality could be able toimage the area of interest and provide metric information. The systemcan include a communication module for communicating imaging data to anexternal device, such as a display device and/or storage device. Thesystem can include a registration module for registering the referenceframe of the image to the reference frame of the magnetic system. Thesystem can then receive the image, register the image, track themagnetic nanoparticles, and provide a means of directing thenanoparticles to be navigated along a desired path, either by anoperator or automatically by a computer controller. The imaging data canbe two-dimensional or three-dimensional. Three-dimensional informationcould be advantageous where navigation occurs in three dimensions. Insome embodiments, the control of the magnetic nanoparticles can occurremotely using the systems described herein.

FIG. 10 illustrates a flow chart of an embodiment of a process 1000 forcontrolling magnetic nanoparticles. At block 1020, the system acceptsthe imaging data from the imaging system. Accepting the imaging data caninclude receiving the information from the imaging system. In someimplementations, the system can request an image and/or direct theimaging system to provide an image at a defined time and/or location.

At block 1025, the system registers its reference frame to that of theimaging system. The imaging system can provide information regarding theposition and orientation of the system to aid in registering thereference frames. Registering the reference frames can includeidentifying or detecting features in an image and comparing them toprevious images to properly align the reference frames.

At block 1030, the system tracks the magnetic nanoparticles. Asdescribed above, the magnetic nanoparticles can include a coating orchemical agent that makes them detectable for a given imaging modality.Using the images received from the imaging system, the control systemcan identify the location of the magnetic nanoparticles. The currentlocation of the magnetic nanoparticles can be compared to previousnanoparticles and the position of the magnetic nanoparticles can betracked over time.

At block 1035, the system plans or determines a navigation path.Planning the navigation path can be automatic and/or based oninformation received from a user. The navigation path can be based, atleast in part, on the imaging data received from the imaging system,patient characteristics, characteristics of the magnetic nanoparticles,the location of the therapeutic target, characteristics of thetherapeutic target, the injection site, or any combination of thesefactors. In various embodiments, the injection site is in any artery orvein (e.g., arteries or veins in the hands, arms or legs, arteries orveins in the neck or shoulder area). Injection may also be performedsubcutaneously or intramuscularly.

At block 1040, the system navigates the magnetic nanoparticles accordingto the navigation plan by positioning the rotating magnet so that therotating magnetic field is oriented properly with respect to a directionof travel and to a therapeutic target site. As described above,positioning the rotating magnet can include automatic positioning by acomputer controller or manual positioning by an operator. The positionof the magnets and/or electromagnets can be controlled in one, two, orthree dimensions and the orientation of the magnets can be controlledalong one, two, or three axes as well. In addition, the system canchange the strength of the magnetic field and/or magnetic gradient andthe variation of the magnetic field and/or gradient, to direct themovement and behavior of the magnetic nanoparticles.

Additional Embodiments of the Magnetomotive Stator System

FIG. 3 depicts an embodiment in which the magnet is made to spin in aplane that is perpendicular to that shown in FIG. 1. Here the permanentmagnet 302, which possesses a North magnet pole 304 and a South magnetpole 306, comprises two support flanges. The first magnet flange 308passes through the first bearing 312 and the second magnet flange 310passes through the second bearing 314. The bearings are supported by amagnet support structure 316. The magnet support structure is connectedto a center shaft 318, which is supported by the support 320 for thecenter shaft. The center shaft 318 is attached to the motor mountingplate 322, to which is attached the drive motor 324. In this embodiment,the magnet drive motor sheave 326 is connected to the drive belt 328.The drive belt 328 is connected to the magnet sheave 330. The supportfor the center shaft 320 is attached to the magnet assembly supportstructure 332.

In some embodiments, the permanent magnet 302 is made to spin in theplane perpendicular to the front face so that the North magnet pole 304and South magnet pole 306 rotate in the same plane. The drive motor 324turns the motor sheave 326, which turns the drive belt 328. The drivebelt 328 then turns the magnet sheave 330, which is attached to thesecond magnet flange 310. The first magnet flange 308 and second magnetflange 310 pass through the first bearing 312 and second bearing 314,respectively. In some embodiments, both magnet flanges 308 and 310 areattached to the permanent magnet 302, thus allowing the drive motor 324to spin the permanent magnet 302.

In FIGS. 4A and 4B, an embodiment of a permanent magnet 436 is depictedthat is capable of being rotated in any plane using a two-motor system.The magnet possesses a North magnet pole 438 and a South magnet pole440. The first motor 402 is attached to the central support 406 via thefirst motor flange 404. Attached to the first motor 402 is the firstmotor pulley 408. The first motor pulley 408 can be connected to thefirst axle pulley 410 via the first motor belt 412. The first axlepulley 410 can be attached to the first axle 414 which passes throughthe first axle bearings 416. At the end of the first axle 414 is thefirst miter gear 418. In one embodiment, the first miter gear 418engages the second miter gear 420. The second miter gear 420 can beattached or coupled to the second miter gear axle 422, which passesthrough the second miter gear bearings 424. The second miter gearbearings 424 are attached to the magnet support yoke 426. The secondmiter gear pulley 428 is connected to the second miter gear axle 422.The second miter gear axle 422 is connected to the magnet pulley 430 bythe magnet belt 433. The magnet pulley 430 can be attached to one of thetwo magnet flanges 432. The magnet flanges 432 pass through the magnetbearings 434. A second motor 442, which is attached to the centralsupport 406 by a second motor flange 444, comprises a second motorpulley 446. The second motor pulley 446 is connected to the second axlepulley 448 by the second motor belt 450. The second axle pulley 448 isconnected to the second axle 452, which passes through second axlebearings 454.

In this embodiment, the first motor 402 turns the first motor pulley410, which transmits the rotation of the first motor pulley 410 to thefirst axle pulley 410 via the first motor belt 412. The first axlepulley 410 can turn the first axle 414, which is made free to turn usingthe first axle bearings 416. Turning the first axle 414 can result inthe turning of the first miter gear 418, which is connected to the firstaxle 414. The first miter gear 418 transmits the rotation to the secondmiter gear 420, which turns the second miter gear axle 422. In oneembodiment, the turning of the second miter gear axle 422 is madepossible using the second miter gear bearings 424. The turning of thesecond miter gear axle 422 results in the turning of the second mitergear pulley 428, which turns the magnet pulley 430 via the magnet belt433. The magnet pulley 430 turns the magnet flanges 432, which resultsin a turn of the magnet 436 around a first axis 437.

In one embodiment, the second motor 442 turns the second motor pulley446, which turns the second axle pulley 448 via the second motor belt450. The turning of the second axle pulley 448 results in the turning ofthe second axle 452, which is made free to rotate using the second axlebearings 454, thus allowing the magnet 436 to be rotated around a secondaxis 456.

FIG. 4C illustrates an embodiment of a permanent-magnet stator system460. In one embodiment, the system 460 allows an angular orientation ofthe magnet to be controlled. In use, the permanent-magnet stator system460 can be positioned near or adjacent to a hemisphere of a patient'shead or near a crown of the patient's head. For example, if the patientis lying down, the permanent-magnet stator system 460 can be placeddirectly behind the head of the patient (e.g., substantially in-linewith an axis extending from the patient's head to the patient's feet).In some embodiments, the permanent-magnet stator system 460 allowscontrol of the angular orientation of a permanent magnet along two axes,denoted as theta (θ) and phi (ϕ) for purposes of this description. Themagnetic system 460 can be placed such that a corner of a magnet 462 ispositioned about 1 mm to about 20 cm from the head of the patient, fromabout 0.1 cm to about 10 cm, from about 0.2 cm to about 5 cm, from about0.5 cm to about 2 cm, from about 1 cm to about 1.5 cm, overlappingranges thereof, or any distance within the recited ranges.

In one embodiment, the permanent-magnet stator system 460 comprises amagnet 462 (e.g., cylindrical or octagonal cylindrical magnet) having anorth and south field alignment that is substantially parallel to aradius of the cylinder or substantially perpendicular to a rotation axis(e.g., a phi-axis). The magnet 462 can be mounted between two slewingbearings. In one embodiment, a first slewing bearing 468 is used tocontrol a first angle (e.g., a theta angle) and a second slewing bearing470 is used to control a second angle (e.g., a phi angle). The slewingbearings 468, 470 can include inner races (not shown). In someembodiments, the inner races of the slewing bearings 468, 470 areattached to worm gears and articulated with a worm controlled by steppermotors 464, 466. Other types of gears or controlled movement mechanismscan also be used, as well as other types of motors, such as servomotors. In one embodiment, a first stepper motor 464 is configured toactuate the theta worm-gear assembly controlling an axis of magnetrotation, or the theta angle. A second stepper motor 466 may beconfigured to actuate a phi worm-gear assembly mounted to a set of bevelgears 472 to rotate the magnet 462 about its axis, the phi angle.

In some embodiments, the worm gears reduce a load on the stepper motor(e.g., the worm gears make it so that there is little or no intermittentload). In some embodiments, the permanent-magnet stator system 460 canoperate to change the theta angle, the phi angle, or bothsimultaneously. For example, actuating the slewing bearings 468, 470such that they rotate in the same direction and with the same rotationalspeed can cause the magnet 462 to rotate about the theta axis. The thetaangle changes because the first slewing bearing 468 is rotating. The phiangle does not change because the set of bevel gears 472 are configuredto rotate when there is relative motion between the slewing bearings468, 470, and in this example there is no such relative motion.Actuating the second slewing bearing 470 while maintaining the firstslewing bearing 468 fixed can cause the magnet 462 to rotate about thephi axis for similar reasons. Actuating the slewing bearings 468, 470such that they have different rotational speeds and/or rotationaldirections can cause the magnet 462 to rotate about both the theta axisand the phi axis. In some embodiments, the permanent-magnet statorsystem 460 can include a linear translation mechanism configured tolinearly translate the stator system 460 (e.g., to position the magnetstator system 460 for treatment of either the left or right hemispheresof the brain). The linear translation mechanism can comprise a screw orthreaded cylinder with a threaded mounting bracket having a hollowcavity that is threaded in a complementary fashion to the threadedcylinder; however, other translation mechanisms can also be used. Thethreaded mounting bracket can be mounted to the system 460 such thatrotation of the threaded cylinder or the threaded mounting bracket cancause the system to translate along a longitudinal axis of the threadedcylinder. The system 460 can be configured to translate at least about 1inch and less than or equal to about 24 inches, at least about 2 inchesand less than or equal to about 12 inches, at least about 3 inch andless than or equal to about 10 inches, at least about 4 inch and lessthan or equal to about 8 inches, at least about 1 inch and less than orequal to about 5 inches.

FIG. 5 is an embodiment of a magnetomotive system comprisingelectromagnetic coils 502. The electromagnetic coils 502 are attached toa support structure 504. Electromagnetic coils 502 can be connected topower supplies 506 via power supply cables 508 and power supply returncables 510. The support structure is connected to a two-segment armpositioner 512. In the illustrated embodiment, power supplies 506deliver power to electromagnetic coils 502 via the power supply cables508 and the power supply return cables 510. The two-segment armpositioner 512 allows the support structure 504 to be positioned inspace. In some embodiments, the power supplies 506 control the amount ofelectric current that is generated within the electromagnetic coils 502.

Robotic Arm

In some embodiments, an arm positioner (e.g., arm positioner 212 and thetwo-segment arm positioner 512) can couple the magnet system to a base(e.g., portable base 202). The arm positioner can be a robotic armcapable of positioning and orienting the magnetomotive system withoutbeing constrained by movement along one or two axes. The arm positionercan provide universal movement. The arm positioner can include motors orother mechanical actuators that allow the arm to be controlled by anelectrical system or by a remote control. For example, the mechanicalcontrol system can allow an operator to control the position of themagnetic system in one, two, or three dimensions through a remotecontrol, computer, electrical controls, or the like. In this way, theoperator can manipulate the position and orientation of the magnet(s) inaddition to manipulating the strength and/or variation of the magneticfield. In some embodiments, the arm positioner can be used inconjunction with the magnetomotive systems depicted in FIGS. 1, 3, and4. In some embodiments, the position of the magnets is controlledthrough other electrical means in addition to or as an alternative tothe arm positioner, such as with cables, rails, motors, arms, or anycombination of these. In some embodiments, the position and orientationof the magnets is controlled at least in part through a five-axisrobotic arm. In some embodiments, the arm positioner provides movementwith six degrees of freedom. In certain embodiments, the electricalcontrol of the position of the magnets can be included in a systemhaving a display coupled to an imaging modality and computer controlsuch that the operator can control the infusion and navigation ofmagnetic nanoparticles in real-time in response to the display andimaging of the patient.

In some embodiments, the robotic arm can be automatically manipulated bythe magnetomotive system. Automatic manipulation allows themagnetomotive system to stow the magnetic system in a substantiallyshielded enclosure, thereby substantially reducing or preventingmagnetic fields of one or more magnets of the system from having aneffect on persons or items outside the system. For example, the systemcan include an enclosure made out of a suitable shielding material(e.g., iron). The automatic manipulation provided by the controller canmove the one or more magnets of the system into the shielded enclosurewhen not in use.

Portable Magnet Pod with Rail Attachment

FIG. 6 illustrates a schematic drawing of an embodiment of a portablemagnet pod system 650 with a bed rail attachment 652. The portablemagnet pod system 650 can be designed to be carried by and secured(detachably or fixedly) to a patient bed or transport device, forexample, in a hospital, urgent care facility, at home, in an ambulance,in a helicopter, or in another emergency vehicle. The portable magnetpod system 650 can be used to control magnetic rotors within the patientin a manner similar to that described herein with reference to thevarious magnetomotive and magnetic systems. The portable magnet podsystem 65 can be placed on, below, or near a patient.

In some embodiments, a portable magnet pod system 650 includes a magnetpod 654 configured to house permanent magnets and/or electromagnets, andthe associated electrical and/or mechanical support and control elementsfor creating a desired magnetic field. The electrical and/or mechanicalcomponents can be similar to those described herein with reference tothe various magnetomotive stator systems. The portable magnet pod system650 can include controls 660 configured to operate the portable magnetpod system 650, for example, allowing an operator to manipulate adesired magnetic field to control magnetic nanoparticles injected into apatient.

The portable magnet pod system 650 can include a rail attachment 652attached (detachably or fixedly) to the magnet pod 654 to providestability. In some embodiments, the rail attachment 652 eliminates aneed to for setting of the patient's supine, or head elevation, angle.The rail attachment 652 can substantially secure the pod to the rail ofa bed, gurney, stretcher or other patient transport device. Insituations where the portable magnet pod is used for a patient sufferinga stroke or has a clot or obstruction in a blood vessel leading to thebrain, the attachment of the portable magnet pod 650 to a rail ensuresthat the magnetomotive system is properly aligned with the central axisof the head and properly positioned aside the affected hemisphere of thebrain. The portable magnet pod 650 can include a handle 662 configuredto allow a user to carry the portable magnet pod 650 to a desiredlocation.

The portable magnet pod 650 can include an integral folding headrest 656pivotably attached to the magnet pod 654. The headrest 656 can bepivoted open when being used on a patient (represented by line 658). Inthe open position, the headrest can aid the operator in properlyaligning the patient and the magnets. This can simplify the operationand/or control of a magnetic control system by ensuring that thepatient's head is at a defined distance and attitude with respect to therotating magnet(s). The headrest can be closed for convenience and easewhile transporting the system. In some embodiments, the portablemagnetic pod includes a dispensable cover for hygienic purposes. Inaddition to facilitating proper alignment, the headrest can prevent apatient from accidentally bumping into the magnet pod 654, therebyreducing likelihood of injury or inadvertent movement of the magnet pod654. The headrest may also insulate the patient (e.g., acoustically,mechanically, electrically) from the magnet pod 654 while ensuring thatthe patient's coordinate system is related to the magnet pd 654 and thetherapy is properly aimed.

Magnetic Tool Rotors

In some embodiments, a therapeutic system is provided for increasingfluid flow in a circulatory system comprising a magnet having a magneticfield for controlling a magnetic tool in the fluid, and a controllerpositioning and/or rotating the magnetic field with respect to thetherapeutic target to rotate an abrasive surface of the magnetic tooland maneuver the rotating abrasive surface to contact and increase fluidflow through or around the therapeutic target. In various embodiments,the circulatory system can be vasculature of a patient, particularly ahuman patient. In some embodiments, the magnetic tool can be coupled toa stabilizing rod, wherein the magnetic tool rotates about thestabilizing rod in response to the rotating magnetic field. In someembodiments, the magnetic tool can include an abrasive cap affixed to amagnet which engages and cuts through the therapeutic target. In someembodiments, the controller positions the magnetic tool at a targetpoint on the therapeutic target, and rotates the magnetic tool at afrequency sufficient to cut through the therapeutic target. The magnetcan be positioned, in one embodiment, such that poles of the magnetperiodically attract the opposing poles of the magnetic tool duringrotation, and the magnetic tool is pushed towards the therapeutic targetby a stabilizing rod upon which the magnetic tool rotates. In oneembodiment, the magnet can be positioned so that the poles of the magnetcontinuously attract the opposing poles of the magnetic tool duringrotation, and the magnetic tool is pulled towards the therapeutic targetby an attractive force of the magnet.

FIG. 11 shows an example use of the magnetomotive stator system towirelessly manipulate a mechanical thrombectomy device (also referred toas a “magnetic tool” above). In this example, a vessel obstruction 830inside a blood vessel 828 is unblocked by a rotating magnet 902 whichpossesses a North magnet pole 904 and a South magnet pole 906 indirections transverse to the axis 908. The magnet 902 follows theexternal magnetic field vector 812, which is generated wirelessly by themagnetomotive stator system. The external magnetic field vector 812changes in time in the direction of the magnetic field rotation angle810. The rotation of the magnet 902 is stabilized by passing astabilizing rod 908 through a hole in the magnet 902. The magnet 902 isfree to rotate about the stabilizing rod 908. In one embodiment, anabrasive cap 910 is affixed to the magnet 902 which engages the vesselobstruction 830. This abrasive cap 910 may use a coating or surfacetreatment that ensures minimal damage to healthy tissue and maximaldamage to the vessel obstruction 830.

In accordance with several embodiments, the use of the magneticgradient, which may be time-varying, and a time-varying magnetic fieldallows for devices to be constructed which possess a magnet capable ofrotating at the distal end. The magnetomotive devices described hereincan be made much smaller and cheaper than existing clinical devices usedto amplify the effects of pharmaceuticals or to bore throughobstructions in the vasculature. Moreover, commercial technologies thatuse a rotation mechanism within a vessel or chamber require a mechanicalor electrical transmission system from the proximal end to the distalend, which can complicate the device, make the device more expensive,and/or increase the overall size. Systems and devices described hereincan generate mechanical action wirelessly at the tip without the needfor a mechanical or electrical transmission system, thereby allowing thedevice to be smaller, simpler, and/or cheaper to manufacture.

For example, the magnetic-based system may be used in a clinical settingfor the enhancement of the effectiveness of a therapeutic agent, such astPA, which is injected intravenously. Magnetic particles (e.g., magneticnanoparticles) can be injected either before or after introduction ofthe tPA within the vasculature, or can be co-administered (e.g.,attached) to a thrombolytic agent (e.g., tPA). The magnetic-basedsystem, which is placed or positioned close to the patient (e.g., withintwo feet, within 1 foot, within 10 inches, within 9 inches, within 8inches, within 7 inches, within 6 inches, within 4 inches, within 3inches, within 2 inches, within an inch of the patient) and near alocation of a therapeutic target (e.g., an obstruction, a clot), can beactivated. In some embodiments, the magnetic-based system would not needto be generating a changing (e.g., rotating) magnetic field at this timein that the gradient would be sufficient to collect particles at thetherapeutic target (e.g., an obstruction, a clot). When magnetic-basedmixing of fluid within the vasculature is desired, the magnetic fieldcan be made to alternate in time (e.g., by rotating one or morepermanent magnets or controlling current through coils of anelectromagnet) which, when combined with the magnetic gradient, whichmay or may not be varying in time, causes the action of the therapeuticagent (e.g., a thrombolytic agent such as tPA) to be enhanced. Inaccordance with several embodiments, a clot or other fluid obstructionor blockage could be destroyed faster and better as compared to existingapproaches. For example, the magnetic nanoparticles can be manipulatedto form a vortex (e.g., predictably circulate) in a region of stagnantflow so that the therapeutic agent (e.g., tPA) is better mixed,resulting in a more efficient drug interaction. Creating a vortex canalso draw in more of the therapeutic agent near the region of turbulentflow in one embodiment.

FIGS. 12A and 12B illustrate an example method of use of a magnetomotivestator system (e.g., FIGS. 4A-4C) and magnetic nanoparticles for thetreatment of a vascular occlusion in the brain 1004, in accordance withan embodiment of the invention. FIG. 12B shows a drip bag 1006 or otherfluid supply and an injection needle 1008 or other introductionmechanism coupled to a conduit or tubing inserted at an injectionlocation 1010 of an arm 1012 of a patient. In various embodiments, theinjection location can be in the arteries or veins in the hands, arms orlegs or arteries or veins in the neck or shoulder area closer to thebrain; however, the injection location may be at any location of thebody (e.g., depending on the target site or patient characteristics). Invarious embodiments, magnetic nanoparticles are introduced from the dripbag 1006 and the therapeutic agent is introduced through the injectionneedle 1008, or vice-versa. FIG. 12A is a close-up schematicillustration of a portion of the vasculature of the brain 1004 includinga blood vessel 828 where blood flow 1002 is unobstructed and an adjacentvessel branch with a vascular occlusion 830 (e.g., thrombus or clot).FIG. 12A also illustrates a rotating magnetic nanoparticle (e.g., FIG.9B) near the vascular occlusion 830. Multiple rotating magneticnanoparticles may facilitate removal, degradation, dissolution,breakdown, erosion, lysis, etc. of the vascular occlusion via thetherapeutic agent. In several embodiments, the magnetic nanoparticles donot contact the vascular occlusion or contact is not the primary causeof action for lysis or removal of the clot. In some embodiments, therotating magnetic nanoparticles (alone or in combination with atherapeutic agent) do not cause fragmentation or embolization of theclot.

In several embodiments, the magnetic nanoparticles and magnetomotivesystem are a mechanical adjunct to the therapeutic agent (e.g., tPA) inthat, the system selectively and rapidly concentrates the therapeuticagent in an occluded vessel. In some embodiments, once the fibrinogennetwork of the clot begins to fragment and blood begins to flow throughthe occluded vessel segment, hemodynamic forces equalize theconcentration of the therapeutic agent moving through the clot, so as tomatch the therapeutic agent concentration in the blood pool. Evidence ofenhanced recanalization can be determined by decreases in NIHSS scores.For example, improvement in NIHSS scores after ten minutes of initiatingtreatment may be double what they typically are for thrombolytic agenttreatment (e.g., IV-tPA) alone (e.g., 8-10 point improvement instead ofa 4 point improvement, on average).

Magnetically-Enhanced Drug Diffusion

FIG. 13 illustrates some examples of how to magnetically enable controlover the diffusion of a therapeutic agent (e.g., a chemical or adjunct)injected into a moving fluidic system (e.g., circulatory system). In theillustrated model, fluid A is travelling and permeates the fluidicsystem (illustrated as the white region in FIG. 13A). At a later time,fluid B is injected (illustrated as the shaded region). FIG. 13Billustrates a problem associated with solely injecting fluid B withoutintroducing and manipulating magnetic nanoparticles-fluid B is limitedin its ability to penetrate the “leg” or branch to reach a therapeutictarget because the velocity of the flow does not travel far into the legor branch. Existing systems then must rely on diffusion to dilutefluid-A with fluid-B. This can take a very long time.

In some embodiments, when magnetic nanoparticles are placed into fluidB, and a magnetic field and gradient are applied (e.g., imposed) to pullsome of the nanoparticles out of the bloodstream into the leg or branch,the nanoparticles take an amount of fluid B with them (as shown in FIG.13C). Time-varying aspects can be changed or varied to amplify thediffusion-facilitating action. For example, the rate of magnetic fieldrotation, the strength of the magnetic gradient, the orientation of thesource field, the size and strength of the magnetic nanoparticle, or anycombination of these can be changed to amplify the action. In time, morenanoparticles can collect at the bottom of the leg or branch and beginto set up circulation patterns (e.g., vortexing patterns), whichdistribute fluid B into fluid A faster than via diffusion alone. Thelonger the process runs, the more nanoparticles are collected, and thestronger the mixing effect becomes, until fluid A is substantiallyreplaced with fluid B at the region of the therapeutic target.

In the case of clot destruction, the leg or branch represents a blocked(e.g., partially or completely obstructed or occluded) vein or artery.In some embodiments, the therapeutic target is a clot in a blood vesselassociated with the brain (e.g., neurovasculature or cerebralvasculature). The blood vessel can be, for example, but not limited to,an anterior cerebral artery, a middle cerebral artery, an internalcarotid artery, a posterior cerebral artery, a vertebral artery, or abasilar artery. As depicted in FIG. 13, to facilitate contact of atherapeutic agent (e.g., thrombolytic drug) with the therapeutic target(e.g., surface of a blocked vessel), the force of diffusion isprincipally involved if the obstruction is sufficiently far from themain flow. Therefore, therapeutic agents (e.g., thrombolytic drugs,chemicals, adjuncts, pharmaceutical compositions) effective insubstantially clearing a fluid blockage from a circulatory system arelimited in their effectiveness; relying on diffusion alone in vivo couldresult in negative clinical outcomes. Because therapeutic agentseffective in substantially clearing fluid blockages from a circulatorysystem may have a relatively short half-life, the use of themagnetomotive stator systems, in combination with the magneticnanoparticles described herein, can speed the process of clearing fluidblockages by the therapeutic agents. If the objective is to deliver atherapeutic concentration of fluid B at the end of the leg or branchwhich is a fraction of the concentration in the main flow, use of thesystems and methods described herein can result in the same therapeuticconcentration of fluid B for a much smaller dose of fluid B initiallyinjected (See FIG. 38). Thus, some embodiments provide enhancedtherapeutic advantages by allowing the use of a smaller dose of atherapeutic agent than would normally be used without the introductionof magnetic nanoparticles controlled by the magnetic-based controlsystems described herein, thereby reducing the occurrence of bleeding oreven death due to excessive doses. For example, the dose of therapeuticagent used on conjunction with the magnetic nanoparticles andmagnetic-based control systems described herein can be less than orequal to about 50%, about 45%, about 40%, about 35%, about 30%, about25%, about 20%, about 15%, about 10%, about 5%, of the standardprescribed dose.

FIGS. 48A and 48B schematically illustrate an embodiment of a beneficialeffect of using the magnetic nanoparticles and magnetic control systemsdescribed herein. FIGS. 48A and 48B illustrate a clot 4830 within avessel branch 4805 near a bifurcation of a parent vessel 4810. The clot4830 is completely blocking flow to the vessel branch 4805. FIG. 48Aillustrates the outcome of infusion of a therapeutic agent 4815 (e.g.,tPA) without introduction and control of the magnetic nanoparticlesusing the magnetic control systems described herein. As shown in FIG.48A, the blood flow is unable to transport the therapeutic agent 4815 tothe clot 4830. FIG. 48B illustrates how the magnetically-controlled rodsor rotors 4820 formed by an agglomeration of magnetic particles generatean artificial current that transports the therapeutic agent 4815 to theclot 4830 within the vessel branch 4805. The artificial current isgenerated by the controlled rotation of the rods or rotors 4820 byembodiments of the magnetic control systems described herein. Asschematically illustrated in FIGS. 48A and 48B, themagnetically-controlled rods or rotors 4820 can be substantiallyelliptical in some embodiments.

In accordance with several embodiments, systems and methods describedherein can be used in a collection mode to manipulate a collection ofmagnetic nanoparticles to translate a stream of the magneticnanoparticles into an occluded branch. In one embodiment, the collectionmode accumulates the desired therapeutic agent at the target. As aresult, a fluidic current can originate from the parent vessel flow'sturbulent region near bifurcation. This flow can draw in a therapeuticagent (e.g., a chemical adjunct) within the bloodstream towards theterminal end of the occluded branch better than by diffusion alone.

As another example, magnetic-based systems and control methods describedherein can be used in a vortexing mode to manipulate the magneticnanoparticles to create a vortex in a region of stagnant flow so that atherapeutic agent (e.g., chemical adjunct) is better mixed within thebloodstream, resulting in a more efficient chemical reaction with afluid obstruction (e.g., due to continuous refreshing of the portions ormolecules of the therapeutic agent that is in contact with the fluidobstruction). In some embodiments, clot dissolution time can beincreased by a factor of three or more when the vortexing mode is used.Such manipulation can be achieved by oscillating a magnetic field indifferent directions (e.g., clockwise, counter-clockwise) at aparticular frequency. For example, the frequency can be greater than orequal to about 0.25 Hz and/or less than about 3 Hz, including but notlimited to between about 0.25 Hz and about 1 Hz, between about 0.5 Hzand about 2 Hz, between about 1 Hz and about 3 Hz, between about 0.75 Hzand about 2.5 Hz, overlapping ranges thereof, less than 3 Hz, less than2 Hz, less than 1 Hz. The vortexing mode of control can enable more ofthe therapeutic agent (e.g., chemical adjunct) to be drawn in near theregion of turbulent flow. In some embodiments, the oscillation can occurbased on visualization or images of the vasculature and/or magneticnanoparticles. In various embodiments, the oscillation is periodic ornot periodic.

In accordance with several embodiments, alternating between thecollection and vortexing modes can result in an improved ability to drawthe therapeutic agent (e.g., chemical adjunct) near a region ofturbulent flow and translate that therapeutic agent more efficientlyinto an occluded branch. In some embodiments, alternating between thecollection and vortexing modes is driven by the point at whichsufficient dose of the therapeutic agent is delivered. In oneembodiment, the sufficient dose can occur when the co-administeredtherapeutic agent is diluted in the blood pool (e.g., via a half-life orfiltering mechanism) or when the therapeutic agent reaches a saturationpoint where additional amounts of the therapeutic agent is no longerbeneficial. In some embodiments, when a sufficient dose of therapeuticagent at the target is reached (e.g., saturation point), the vortexingmode is the best mode of action.

Alternating between the collection mode and the vortex mode can includealtering the magnetic gradient and/or the time-varying magnetic field tocause the magnetic nanoparticles to behave differently. For example, inthe collection mode, the magnetic gradient can be increased and thetime-varying magnetic field can be decreased such that the magneticnanoparticles experience a net force that results in the magneticnanoparticles substantially accumulating at a desired location. Asanother example, in the vortexing mode, the magnetic gradient and/or thetime-varying magnetic field can be adjusted such that the magneticnanoparticles experience a time-varying net force that results incirculating motion and/or angular velocity within a desired region.Thus, by changing the magnetic field properties (e.g., the magneticgradient, the magnetic field strength, orientation of the magneticfield, direction of the magnetic field, etc.) as a function of time, themagnetic-based systems and control methods can be used in and switchedbetween collection mode, vortexing mode, navigation mode, or somecombination of modes. In some embodiments, a dose of therapeutic agentis locally delivered to the target site by the clinician and thevortexing mode is the only mode necessary, similar to local delivery oftPA at a target site of a clot through a microcatheter.

In the case of the magnetic tool, the system is capable ofadvantageously grinding away large volumes of thrombus or other blockagematerial, such as atherosclerotic plaque material, quickly and veryprecisely. In accordance with some embodiments, a 2 French hole (⅔ mm)can be cut through a mock atherosclerotic clot using an embodiment ofthe wireless magnetomotive stator system. With respect to the use ofmagnetic nanoparticles, embodiments of the systems described herein canallow for more precise control of magnetic nanoparticles to create arelatively “gentle” scouring action that allows the leaf valves in theveins to remain intact and undamaged. With respect to the magnetic tool,this action can be used in combination with thrombolytic drugs to removeclot material in an occluded artery or vein in some embodiments. Whenused with a thrombolytic drug to treat a blood clot, the thrombolyticdrug could be helpful when mechanical action is intended to beminimized. Using magnetic nanoparticles, the material removed from theblocked vein can be captured with a small magnet on a guide wire.Depending on the mode of operation, the removed material has beenobserved to be small (less than 1 mm size clot particles), or ballmixtures of clot material, drug and magnetic nanoparticles. Both themagnetic nanoparticle collection and magnetic tool objects are capableof being visualized with standard imaging technologies allowing forcomputer-reconstructed path planning.

Furthermore, imaging and/or other diagnostic technologies can beincorporated into (e.g., communicatively coupled to) the magneticcontrol system such that an operator can have real-time feedback of theposition of the magnetic nanoparticles, thereby allowing for dynamiccontrol and navigation. The real-time feedback provided by imagingand/or other diagnostic technologies can increase the effectiveness ofthe process, for example, by providing adjustment of parameters of therotating magnetic field (e.g., orientation, position, rotationfrequency) and/or the magnetic gradient, by introducing morenanoparticles and/or by introducing increased quantities of therapeuticagents.

The real-time feedback can include information related to theconcentration of therapeutic agent in a particular location (e.g.,adjacent a fluid obstruction of an obstructed blood vessel), informationrelated to the concentration of magnetic nanoparticles or nanorods in aparticular location (e.g., adjacent a fluid obstruction of an obstructedblood vessel), which may be correlated to or indicative of theconcentration of therapeutic agent at the location, images of the fluidobstruction, information related to fluid flow through an obstructedblood vessel, and or other information. The information received throughthe imaging technologies can be used to determine when to switch betweenthe collection and vortexing modes, which can be performed manually byan operator or automatically by a computer controller. For example, ifit is determined that a concentration of therapeutic agent or magneticnanoparticles or nanoparticle rods is low at a location adjacent atherapeutic target, the magnetic control system can be switched to orremain in the collection mode to increase the concentration levels. Ifit is determined that a concentration of therapeutic agent or magneticnanoparticles or nanoparticle rods is sufficient, the magnetic controlsystem can be switched to or remain in the vortexing mode. In oneembodiment, the real-time feedback is provided by tuning an externalDoppler ultrasound system to the rotational frequency of the magneticnanoparticles.

FIG. 14 illustrates an embodiment of a magnetic field generator. In thedepicted figure, the generator 1200 comprises a permanent magnet source1205 with North 1206 and South 1207 poles, mounted so that two separaterotations about axis 1210 and about axis 1215, respectively, areenabled. For spin about axis 1210, magnet source 1205 is rotated bypulley belt 1225, which is driven by geared shaft 1226, which in turn isdriven by driving gear 1230. Gear 1230 is mounted on thrust bearing 1235and driven by motor 1240 mounted on rotor system 1225, 1226, 1230 thatenables rotation about the spin axis 1210 using a motor 1245. A separatedrive system enables rotation about second axis 1215 using components1220, thrust bearing 1235, and motor 1240. The generator is positionedwith the jointed arm 1250.

In some embodiments, the jointed arm 1250 is a robotic arm, configuredto move translate the generator 1200 in one, two, or three dimensionsand/or rotate the generator along one, two, or three axes. The jointedarm 1250 can include one or more joints to facilitate positioning andtranslation of the generator 1200. In some embodiments, the jointed arm1250 allows for unrestricted free motion that is not dependent onmovement along or about fixed axes. The jointed arm 1250 can beconfigured to move automatically and/or through operator remote control.The generator 1200 advantageously provides simplicity, smaller size, andlower cost in accordance with several embodiments.

In some embodiments, the generator 1200 has additional features wherethe simplicity of the design of generator 1200 is not desired. Thegenerator 1300 depicted in FIG. 15 displays an example of such anembodiment. FIG. 15 is a schematic drawing of an embodiment of a fieldand gradient generating device. FIG. 15 is a block diagram of a magneticfield generator 1300 surrounding a human leg 1360 having a blood vessel1355 with an obstruction 1350. Three coils, 1301, 1302, and 1303, arefed currents from drivers 1311, 1312, and 1313, through connections1321, 1322, and 1323, respectively. Drivers 1311, 1312, and 1313 arecurrent sources controlled separately by a distributing circuit 1330,which receives information from a computing device 1335. Currentsources, 1311, 1312, 1313, can be capable of generating a sine wavecurrent sufficient to provide the peak magnetic field desired. In someembodiments, the peak magnetic field is less than or equal to about 0.3Tesla. If different magnetic field characteristics are desired inindividual cases, the currents may have more complex temporal variationsthan sine waves. As determined by computing device 1335, in response tooperator input 1341, the distribution and types of currents and theirsequences to the coils can be calculated by the computing device 1335.The specific operational instructions from programs stored in memorycommunicatively coupled to the computer 1335 are based on knowledge ofthe particular operation, with specific instructions thereby providedfor operating according to the procedure input by the operator (e.g.,physician). The generator 1300 advantageously provides added flexibilityin the type of fields generated from the more complex magnetic fieldsources and the computer input, and the added refinement to the newprocedures.

Two major classes of blockage in the medical cases to be treated bymethods described herein are partial and total. Partial blockage yields,in general, low blood flow, while total blockage results in no bloodflow. In both cases, the effectiveness of a drug delivered to remove theclot by conventional means is generally difficult and inefficient. Majorlimits to conventional methods of removing the blockages include thedifficulty of effective drug action on an occlusion, the incompletenessof removal of dislodged material, damage to vessels and adverse effectsof downstream components of the removed material. FIGS. 16A and 16Bexhibit the underlying physical reasons for the difficulty andinefficiency of conventional treatments of a blood clot, and for whichthis disclosure provides major improvement. For example, in accordancewith several embodiments, the systems described herein magneticallymanipulate the magnetic particles to form larger structures so that theyact as “stirring rods” and establish a flow of blood towards theoccluded vessel branch, thereby greatly amplifying therapeutic agentdiffusion and accelerating clot destruction. The systems and methodsdescribed herein can reach areas otherwise inaccessible or unreachableby conventional methods of delivering drugs alone due to the lack ofblood flow to carry the drug to the treatment region and solve thelimits or constraints (such as those described above) of using drugtreatment alone in some embodiments.

FIG. 16A is a cross sectional view of a typical accumulation ofoccluding material in a bend of a section of a blood vessel 1400 havingno flow, illustrating a common difficulty in using a drug (e.g.,thrombolytic drug) for dissolving the occluding material. Adjacent avessel wall 1405 is a target region of deposited occluding material1410, the “clot,” with internal boundary edge 1415. In the depictedexample, the physician or other medical professional has introduced adrug 1425 in the vicinity of the clot. FIG. 16A exhibits the typicalsituation of a stagnant action layer 1430 of partially interactingmaterial and a layer 1435 of more concentrated but less effective drug.Layers 1430 and 1435 separate the clot from the more concentratedthrombolytic drug 1425 that had been injected into the vessel 1400 inthe general region of the target region. Motion and distribution of thedrug can arise from thermal agitation and slow dispersion as a means ofrefreshing contact between the clot and the injected drug, which makesthe action extremely slow and inefficient. Some practitioners haveintroduced metal stirrers, venturi flow-based jets, and sound-basedagitation technologies to increase efficiency, but the difficulties andlimitations of those methods have been documented.

FIG. 16B is a cross section view of a target occlusion 1455 formedagainst a wall 1460 of a vessel 1465 having a stiffened valve leaflet1470, with low blood flow in a region 1480 and with relatively low fluid(mixed blood and drug) flow at the clot surface 1457. As a result, thereis relatively little interaction between the clot and a drug 1475injected upstream into the region 1480. One approach could be toincrease the quantity of drug 1475 injected upstream, but this may beundesirable due to potential adverse effects caused by increased drugdose and/or cost. Other typical approaches involve closing off thevessel and slowly injecting a thrombolytic agent, with slow, inefficientdissolving of the clot, and the injection of large quantities ofthrombolytic drug, thus exhibiting approximately the same difficultiesof the case with blocked vessel (e.g., vein). Some treatments provideartificial mechanical, venturi flow-based, and sound-based agitation inregion 1480 in attempts to enhance the efficiency of interaction at theclot surface 1485. Catheters with jets may spray thrombolytic drugs inattempts to get more efficient dissolution of the clot. Removal of theoccluding material is sometimes performed by insertion of mechanicaldevices, with considerable difficulty and with danger to the valve. Allof these methods may be helpful in some cases, but are generally oflimited effectiveness.

FIGS. 17A through 17C exhibit the underlying process, according to someembodiments, in the development of nanoparticle rods from chains ofmagnetic nanoparticles. FIGS. 17A-17C show a cross section of thesequence of structuring of coated or uncoated magnetic nanoparticleswith increasing magnetic field. Increase of the field during a risingpart of the cycle may cause more and more nanoparticles to align intolonger nanoparticle rods.

These are shown with zero field in FIG. 17A as nanoparticles in a randomdisposition of particles 1505, arrayed so as to be roughly evenlydistributed in space, and having a certain statistical fluctuation inposition. In FIG. 17B, when a small external magnetic field 1510 isapplied to the same group of nanoparticles, they are formed into a loosearray 1515 of short, oriented magnetic “rods.” At a certain larger field1520, depending on nanoparticle size and coating, shown in FIG. 17C, thesame nanoparticles aligned as magnetic rods 1525 have become longer. Inthis figure, the rods are depicted as uniform in size although that isnot strictly the case, nor is it necessary. This magnetic process can beviewed in two ways: a) the field increase from FIG. 17A to FIG. 17Bbeing that in a single (slow) cycle of magnetic field alternation, or b)the increase over a number of cycles as the peak-to-peak magnitude ofthe field generated is increased. Depending on the absolute scale andoscillating frequency, the actions are not reversed during a given cycleof oscillation.

In general, the method applies magnetic fields of greater than or equalto about 0.01 Tesla and/or less than or equal to about 1 Tesla,including but not limited to from about 0.01 Tesla to about 0.1 Tesla,from about 0.05 Tesla to about 0.5 Tesla, from about 0.1 Tesla to about0.6 Tesla, from about 0.3 Tesla to about 0.9 Tesla, from about 0.5 Teslato about 1 Tesla, overlapping ranges thereof, less than 1 Tesla, lessthan 0.5 Tesla, less than 0.25 Tesla, less than 0.1 Tesla. Gradientstrength can be greater than or equal to 0.01 Tesla/m and/or less thanor equal to 10 Tesla/m, including but not limited to from about 0.01Tesla/m to about 1 Tesla/m, from about 0.01 Tesla/m to about 3 Tesla/m,from about 0.05 Tesla/m to about 5 Tesla/m, from about 1 Tesla/m toabout 4 Tesla/m, overlapping ranges thereof, less than 5 Tesla/m, lessthan 3 Tesla/m, less than 2 Tesla/m, less than 1 Tesla/m. In general,rods can have a length that is greater than or equal to about 0.05 mmand/or less than or equal to about 3 mm in length, including but notlimited to from about 0.05 mm to about 2 mm, from about 0.1 mm to about2 mm, from about 0.2 mm to about 1.5 mm, from about 0.2 mm to about 1mm, from about 0.3 mm to about 0.9 mm, from about 0.4 mm to about 0.8mm, overlapping ranges thereof, less than 3 mm, less than 2 mm, lessthan 1.5 mm, less than 1 mm.

At a certain rotating magnetic field strength and field rotationfrequency, depending on nanoparticle size and coating, the rods willreach a saturation field and achieve a maximum length, developing asdepicted in the graph of FIG. 18A. The rod growth is not necessarilyexact, and the curve illustrates a general nature of the growth. Fullydeveloped rods may contain a number of nanoparticles, as many as 10 ormany more, depending on their size, and the magnitude of the rotatingmagnetic field. The rods are not stiff, depending on the magnetic fieldand gradient, and on the amount of magnetite in each nanoparticle aswell as the nanoparticle size. Other materials may be attached tonanoparticles for chemical, magnetic, and imaging reasons. That chemicalcan be a thrombolytic drug. The thrombolytic drug can also be injectedindependently.

When a magnetic field is imposed on a collection of magneticnanoparticles, they can combine to form larger structures. The size ofthese assembled structures can be related to an applied magnetic fieldstrength, a size of the magnetic nanoparticles, and/or a thickness of acoating on the magnetic nanoparticle. FIG. 18B illustrates agglomerationof magnetic nanoparticles into an assembled structure (e.g., a stir rod)as a result of the applied magnetic field. The magnetic nanoparticlescan become magnetized and align due in part to the applied magneticfield. As the applied magnetic field increases in strength, the magneticnanoparticles can continue to become magnetized and align, assemblinginto a larger structure, such as the rod depicted in FIG. 18B. Themagnetic nanoparticles can become saturated at a magnetic field strengthwhere the magnetization and alignment of the nanoparticles remainssubstantially constant. In one embodiment, for uncoated magnetitenanoparticles, the particles are close to a saturation point when theapplied magnetic field is approximately 0.2 T. In some embodiments,nanoparticle size can affect the strength and/or rigidity of theassembled structure. For example, when an assembled structure has anangular momentum, a likelihood that the assembled structure (e.g., rod)will break apart is inversely related to the size of the magneticnanoparticles making up the assembled structure. In some embodiments, arotation frequency between 1 Hz and 10 Hz (e.g., between 1 Hz and 5 Hz,between 2 Hz and 4 Hz, 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9Hz, 10 Hz) facilitates formation of nanoparticle rotors or rods of asuitable size to generate sufficient artificial currents within bloodvessels without causing the nanoparticle rotors or rods overly large.

FIG. 18C illustrates an assembled structure, such as a rod, rotating andtranslating as a result of a time-varying magnetic field. In someembodiments, the time-varying magnetic field can rotate and can have amagnetic field gradient. This combination can result in a torque and anet force on the rod. Due in part to the torque, the rod can rotate. Therotation and the net force can result in a forward translation of therod as illustrated.

FIG. 18D illustrates a rod rotating and translating across a surface asa result of a time-varying magnetic field. If the rod comes into contactwith a surface, a combination of the torque, force from the magneticgradient, and friction between the rod and the surface can result in aforward translation. The motion of the rod can be end-over-end, similarto an ellipse rolling along a surface.

FIG. 18E illustrates flow patterns arising from the rotation andtranslation of one or more rods. As described with respect to FIGS. 18Cand 18D, a rod can rotate and translate as a result of a time-varyingmagnetic field having a gradient. The rod can rotate and translate in aforward direction when in contact with a surface, to the right in FIG.18E. Due in part to the rotation and translation of the rods, a flow canbe generated in a surrounding fluid. As the rod translates forward itcan experience a change in magnetic field. In some embodiments, themagnetic field can diminish with translation distance. As the gradientdiminishes, the downward force on the rod can diminish. If the forcediminishes past a threshold value, the rod can cease to be in contactwith the surface, resulting in no friction force between the surface andthe rod. The rod can then experience a pressure arising from a flow ofthe fluid medium which surrounds the rod. This flow can result in atranslation that is roughly backward, or left in FIG. 18E. As the rodmoves backward, the magnetic field gradient which the rod experiencescan increase and the rod can be pulled back to the surface. Once back tothe surface, the rod can move forward in an end-over-end manner asexplained above. The overall motion of the rod can be generally circularor elliptical in nature. During this process, the rod can rotate due inpart to the time-varying magnetic field. A combination of the rotationof the rod and the generally circular motion of the rod can result in aroughly circular or elliptical flow pattern. In some embodiments, thisflow pattern can increase mixing of a therapeutic agent or increaseexposure of a therapeutic target (e.g., a clot) to a therapeutic agent(e.g., a thrombolytic agent).

FIG. 19 illustrates geometric features of the end-over-end walk of asingle rotating rod acting from application of a rotating magnetic fieldemanating from a fixed source in space. It displays a sequence of 8positions of a single rotating rod as it rotates and walks, so as toexhibit the directions of field and pulling force of the gradient. It isto be understood that the effective magnetic moments of individualnanoparticles are substantially continually aligned with the localmagnetic field, so that they maintain the interactions to retain the rodand its magnetic moment, while the field and rod are rotating, that is,maintaining alignment of the rod with the field.

Without being bound by a particular theory, and as will be discussed inthe following section in equations [1] and [2], the field B establishesa torque, but it does not exert a pulling force on the rod moment, whilethe gradient G exerts a pulling force but no turning torque on themoment. Therefore, a rotating magnet source will have a pulling gradienttowards it, shown as the downward arrows in stages shown in FIG. 19.Smaller magnetic nanoparticles, generally below about 150 nm indiameter, act primarily as magnetically permeable materials, which willsubstantially align with the local field without individually rotatingin space. In any case, they will form the rods as described above, whichthemselves have moderate rigidity on the nano-scale, but are very softin the millimeter scale of treatments. In FIG. 19 trigonometric labelingillustrates the geometrical (angular) aspects of changing components ofthe force and torques on the nanoparticles as related to the walk of therod towards the right in response to the rotating field. In other words,the rods act approximately as fixed magnetic rods. In FIG. 19, the fielddirection in each of the 8 positions, is shown by arrows 1701, 1711,1721, 1731, 1741, 1751, 1761, 1771 as the field rotates clockwise. Therod magnetic moments 1702, 1712, 1722, 1732, 1742, 1752, 1762, 1772follow that direction. In the stages shown in FIG. 19, however, thearrows 1703, 1713, 1723, 1733, 1743, 1753, 1763, 1773 point downwardtowards the center of the rotating field source, representing themagnetic gradient according to equation [2] below. On the scale of therod lengths, about 2 mm, the movement to the right is small relative tothe distance to the source magnet.

FIG. 20 illustrates the development of a limit to the concentration ofmagnetic rods when the source magnetic field is rotating about a fixedposition of the source magnet. The gradient, unlike the field, may pulltowards the magnetic center of the source. The field B itself creates atorque τ of alignment on a magnetic dipole moment μ:

τ=μB sin ϕ,   [1]

where ϕ is the angle between the direction of the magnetic moment μ andthe magnetic field B. A uniform field without gradient will not create anet force on the moment μ. However, a gradient G will create a force Fon magnetic moment μ according to:

F=μG cos ϕ,   [2]

where ϕ is the angle between the direction of the moment μ and of thegradient G.

FIG. 20 shows the nature of the spatial “resolution” of the system in anopen location for the rods. For a fixed location of the rotating magnetsource, the pull towards it from the gradient will change direction asthe rods 1805, 1806 and 1807 walk to the right. They will have increasedtheir distance from the source, resulting in a loss of strength of thefield. In FIG. 20, as the rotating external field source will haveremained at the left shown by arrow 1810, the rod locations have movedto the right of the fixed rotating magnet (below and off screen in FIG.20). At the stage shown here, the arrows depicting the three rods 1805,1806, and 1807 have moved far to the right from the center of therotating source magnet system. Relative to their size and their distanceto the magnet source, this distance to the right has increased so thatthe field source and gradient are at an angle and are reduced inmagnitude. The gradient, in the direction shown by large arrow 1810,pulls on the nanoparticles and rods, which are driven by the tractionprovided according to the force of equation [2] at their locations. Thegradient G can fall off with distance from the source, typically by afactor between the inverse cube and inverse fourth power of distance,while the field B is falling off with distance from the source roughlyas the inverse cube of distance from the source center. In this walking,the force caused by the magnetic gradient is reducing which is used topull them down onto a walking surface. As a result, they can ultimatelylose traction. For a fixed location of the magnet source, thedistribution of particles begins to approximate a Gaussian distribution.This distribution of particles can be used to describe the spatialresolution of the system.

The resulting motion of the magnetic nanoparticles in the presence ofthe gradient G can be more easily described if the gradient G isrepresented as a vector having a component pointing perpendicular to thedirection of walking motion (e.g., down in FIG. 20) and a componentpointing parallel to the direction of walking motion (e.g., left in FIG.20). Once the magnetic nanoparticles travel a sufficient distance alonga surface such that the perpendicular component of the magnetic gradientG no longer provides sufficient force to maintain traction against thesurface, the magnetic nanoparticles can lose traction and changedirection. In some embodiments, the change in direction occurs due tothe parallel component of the gradient G, which acts to provide a forceon the magnetic nanoparticles opposite the walking direction and towardsthe magnetic source. As illustrated in FIG. 20, the gradient 1810 wouldcause a force to the left on the magnetic nanoparticles which wouldresult in motion to the left because the magnetic nanoparticles nolonger have sufficient traction against the surface to walk to theright. In some embodiments, the change in direction occurs when themagnetic nanoparticles no longer have sufficient traction against thesurface to walk along said surface as illustrated in FIG. 19, and afluid flow in the region causes the magnetic nanoparticles to move in anopposite direction. In some embodiments, the change in direction iscaused by both the magnetic gradient and the flow in the region. Oncethe nanoparticles have traveled a sufficient distance in the oppositedirection, and if the magnetic gradient G is of a sufficient magnitudeand direction, then the magnetic nanoparticles can again gain tractionagainst the surface and walk along the surface in the original direction(e.g., to the right in FIG. 20). Repeating this sequence can cause themagnetic nanoparticles to move in a circulating, or vortexing, motion.

A consequence of the action described in FIG. 20 is that, for a fixedlocation of the rotating magnet source, the reduction in force withdistance as the rods walk can result in a Gaussian-like distribution ofrod activity where the arrow 1810 simply points to a region of maximumdensity at closest location to a magnet, and represents the positiondependence of the rod walking, which is of maximum strength when therods are closest to the magnetic source.

The magnetic mechanics of a single rotating rod provide the “soft brush”quantities according to the following calculations. It is to beunderstood that these conditions apply directly for rod bundles thathave relatively sparsely attached clot material. Discussed below is auseful mode of operating rods in a rotating field in which the clotmaterial is allowed to become bundled with the rods, leading to softclumps that are stable and magnetically removable. Such a mode will notfollow the calculations of this section. Nevertheless, the calculationsof this section show the underlying behavior of the rotating scouringrods when lightly loaded, and a mode that may be used in cases of smallocclusion material, or cases where the delicacy of the procedure or sizeof vein or artery may not allow clumps of material to be endured. Suchcases may arise in some occlusions in the brain.

Here, for simplicity, the rods are treated as rigid. FIG. 21A is adiagram exhibiting trigonometric detail of the creation of rotationalforce and energy on the rotating rods that in turn creates turbulence toenhance drug mixing and interaction with the surface of the clot. Theelements of the action of the magnetic rotating field B are shown at agiven moment on a single rod of magnetic moment p in a plane defined bydirections of the rod magnetic moment, and the direction of the field Bat an instant when B is directed at an angle β from the x-axis. At thisinstant the (constant) moment μ is directed at an angle θ from thex-axis. Therefore, at this instant the magnitude of the torque τgenerated on the moment μ by the external source magnet is given by:

τ=μB sin(β−θ),   [3]

FIG. 21B shows, in coordinates centered at the center of a symmetricalrod, the angular force F(θ) exerted on the rod, which is assumed to besymmetrical. This assumption is practical when the rod size is smallcompared with the distance to the magnet source. The resulting force:

F _(θ)=2μ(BIL)sin(β−θ)   [4]

is generated by the field B at the ends of a rod of length L.

A drag force might be approximated from standard mechanics with angularvelocity dependence (dθ/dt)², that is:

F _(drag) =−C(dθ/dt)²   [5]

where C is a proportional constant. Under that assumption, the finalequation of motion for a symmetric rod is:

(mL/4)d ² θ/dt ²)=2μBIL [sin(β−θ)]−C(dθ/dt)²   [6]

Further, defining an angle α=β−θ and letting β=wt, with ω an angularrotational frequency of the magnetic field B, then α=β−θ and therefore,d²α/dt²=−d²θ/dt². Equation [3] becomes:

(mL/4)(d ² θ/dt ²)=2μBIL sin α−C(ω−dα/dt)²   [7]

For a constant lead angle α, this simplifies to:

sin α=CLω ²/2μB   [8]

A maximum frequency ω_(o) that preserves a constant lead angle α is

ω_(o) ²=2μB/CL,   [9]

where α=π/2, that is, 90 degrees.

At some angular frequency greater than ω_(o) the moment μ cannot followthe field rotation and the system becomes destabilized. At much higherfrequency, the motion substantially halts, since half of the time thefield leads by less than π/2 and for the other half of the time it leadsby greater than π/2. Thus, the two torques effectively cancel. From thisreasoning the kinetic energy will show a frequency dependence such asshown in FIG. 21C. Specifically, the kinetic energy T is:

T=2×(½)(m/2)(L/2)²(dθ/dt)²   [10]

FIG. 21C is a graph expressing this dependence of kinetic energy of therod on frequency of rotation in which the maximum energyT_(o)=(ml²/8)ω_(o) ² where ω_(o)=dθ/dt. That is, the peak rotationalkinetic energy available for a single rod depends on the rod mass,length, and is quadratic in the angular velocity up to the point wherethe rod cannot follow the field rotation.

With the above understanding of the formation and mechanical behavior ofa rod of magnetic nanoparticles, the use of the system and methods as itapplies to medical applications can be shown. The system ofnanoparticles has been found to behave (and appear visually) as a groupof flexible magnetic rods acting on occlusions in blood vessels. First,the treatment of the two characteristic problematic cases discussed withFIGS. 16A and 16B, above, will be shown with the introduction ofrotating rods.

FIG. 22A illustrates a practical benefit of the introduction ofturbulence with spinning rods. FIG. 22A illustrates a portion of avessel having complete spatial blockage being treated using the methodsdescribed herein, in contrast to the conventional treatment illustratedin FIG. 16A. FIG. 22A is a cross section view of lumen 2000 with noflow, having a clot 2005, with a fresh supply of thrombolytic drug 2010being injected near the occlusion. Three spinning magnetic rods 2030(not to scale) have been shown injected along with the fresh drug 2010,and they generate local turbulence as they are pulled in the direction2025 of a rotating magnet source (not shown here). With a clockwisespinning rotation the rods are shown co-mingling with the fresh drug,and brushing the surface of the clot 2005 as they move slowly to theleft as the external rotating magnetic field source moves. The tinyparticles of clot 2005 accumulate at the right 2035, where they willform a ball, when the rotation is continued, as illustrated in FIG. 23A.

In some embodiments, the removal (e.g., lysis, destruction, breakdown,dissolution, maceration) of the clot 2005 occurs without mechanicalscouring of the clot material. In some embodiments, the principalmechanism for removal of the clot 2005 is not the abrasion of themagnetic rods 2030 scraping pieces of the clot 2005. In someembodiments, the principal mechanism for removal of the clot 2005 is notdue to hyperthermia caused by inductive heating of the magnetic rods2030 arising from an alternating magnetic field. In some embodiments,the magnetic rods 2030 do not have an abrasive coating. In someembodiments, the magnetic rods 203 have a non-abrasive coating. Thesituation is to be compared with that of FIG. 16A, in a staticapplication of drug that would have little mixing action, and mustdepend on lengthy time for removal of the clot. In some embodiments, themagnetic nanoparticles can be manipulated to form a vortex (e.g.,predictably circulate or oscillate) in a region of stagnant flow tobetter mix an adjunct, resulting in a more efficient chemicalinteraction. Creating a vortex can also draw in more of the adjunct nearthe region of turbulent flow. The circulation can occur at a frequencygreater than or equal to about 0.1 Hz and/or less than or equal to about5 Hz, or a frequency greater than or equal to about 0.25 Hz and/or lessthan or equal to about 3.5 Hz, overlapping ranges thereof, 1 Hz, 2 Hz, 3Hz, 4 Hz, or 5 Hz.

FIG. 22B is a cross section view of the upper part of a lumen 2050 inwhich example embodiments of methods and devices are shown solving theproblem of inefficient clot removal by standard methods in the case asshown in FIG. 16B. This case might represent partial blockage in a legartery or cardiac chamber. In some embodiments, there is slowly flowingblood 2090 in the partially blocked lumen 2050, as was exhibited in FIG.16B. Clot material 2058 and 2062 has built up around valve leaflet 2060,stiffening it and causing significant but not total flow reduction. Inthis case, the vessel 2050 is not totally closed, and the reduced flowis due to the partial occlusion and rigidity of rigid valve 2060. Asdescribed in relation to FIG. 16B the blood flow, though slow, carriesoff injected drug with inefficient contact with the occluding material.In some embodiments of the method, the actions of rotating scouring rods2055 acting on clots 2058 and 2062 can be shown to greatly increase thedrug contact, as well as provide gentle scuffing on a small scale.Turbulent flow in regions 2080 and 2085 is generated by the rotatingrods 2055 whose relatively small and flexible structure can work in suchregions without substantially or significantly damaging the vessel wall2070 or valve leaf 2060. In some cases the removed magnetically infusedmaterial will be collected downstream by magnetic means.

In some embodiments, a principal mechanism for removal of the clotmaterial 2058 and 2062 is not the abrasion of the rotating rods 2055scraping pieces of the clot material 2058 and 2062. In some embodiments,the principal mechanism for removal of the clot material 2058 and 2062is not due to hyperthermia caused by inductive heating of the rotatingrods 2030 arising from a time-varying magnetic field. In someembodiments, the magnetic rods 2030 do not have an abrasive coating. Insome embodiments, the rotating rods 2030 have a non-abrasive coating.

When the rotation is continued under certain conditions (especially lowflow) the clot material and magnetic nanoparticles can form a magneticball, as described in FIG. 23B below. Again, without being bound by aparticular theory, it is believed that as the magnetic nanoparticlescirculate they may engage the surface of the thrombus. As the thrombusbreaks into tiny pieces, the magnetic nanoparticles become encapsulatedin or otherwise form a combination structure (e.g., ball-like or othershaped structure) that comprises the magnetite and thrombus materials.This combination structure has one or more advantageous properties, inaccordance with some embodiments of the invention. For example, (i) thecombination structure can accelerate the destruction of the thrombus byincreasing the surface area of interaction and by causing more efficientcirculation of the thrombolytic drug; (ii) the structure can capturesmaller emboli, encasing them in the ball structure, thereby preventingthem from escaping; (iii) the structure can continue to break downslowly as that structure is lysed by the thrombolytic drug; and (iv) thestructure can be recollected with a magnet-tipped device, therebycapturing the larger emboli and the magnetic nanoparticles.

In some embodiments, with an appropriate rate of delivery of a drug,depending on the nature and age of a clot and of magnetic rodinteraction, the magnetic rod scouring process can be arranged to mixclot material and rods, as described, to provide small, roughlyspherical balls of clot material combined with the magnetic rods. Thoseconditions can be determined by the rate of application andconcentration of the thrombolytic drugs during the magnetic procedure.In one embodiment, the rate of delivery of drug is varied in order toform the combination structure (e.g., ball) of desired or optimalproperties (stiffness and size) for completion of the removal.

An example application of this technique is described as follows. FIG.23A is a cross section view of a blood vessel 2120, totally occluded bya clot 2130, with no blood flow. Here, magnetic rods 2122 are stirringthe region just proximal to clot 2130 with clockwise rotation of themagnetic field, causing circulation pattern 2135. The mixing region 2125contains a mixture of clot material, thrombolytic drug, and a smallamount of magnetic rod material.

In the cross section view of FIG. 23B, this rotational interaction inblood vessel 2120 has continued and a structure (e.g., ball) 2140 beginsto form of material stripped from clot 2130 using captured emboli, and asmall amount of magnetic rod material.

In FIG. 23C, the rotating ball 2140 has become enlarged and acceleratesthe therapy. It has opened the blocked channel in vessel 2120, leavingminor remains 2150 of occlusion material. The ball 2140 is stillrotating and held in location by the force from the gradient of therotating magnetic source (e.g., magnet).

FIG. 23D shows the means of capture and removal of completed clot ball2140. At an appropriate time, before restored blood flow has pushed thethrombus ball 2140 downstream, a magnet-tipped probe 2145 is insertedand captures the ball structure 1040 for removal by retracting themagnet-tipped probe 2145.

FIG. 24 is a cross section view of blood vessel 2255 containing valveleaflets 2260, one of which, 2262, has occluding material 2263 that hasstiffened valve 2262 to become non-functional. Blood is flowing slowlyin the direction of arrow 2270. An external magnetic field generator,(such as depicted in FIG. 14 or FIG. 15), has generated a rotating fieldin this region into which rotating nanoparticle rods 2275 are acting onclot deposits 2263 in the manner shown, for example, in FIG. 22B above.The magnetic nanoparticle rods 2275 shown may actually be members of alarge number of such rods in the space adjacent the clot deposits 2263.The rods 2275, in one embodiment, are flexible and can be brushed tolengths shorter than the approximately one to two millimeters asdescribed above, in order to function on the narrow corners of the clotdeposits 2263. In several embodiments, the rods 2275 have functioned toremove material in model spaces that were approximately 2 centimeterswide and 3 millimeters deep and removed approximately 100 cubicmillimeters of thrombus material. In some embodiments, the rods areconfigured to remove or loosen at least 25%, 50%, 60%, 75%, 85%, 90%, or95% of the thrombus material by directly contacting the thrombus orwithout direct contact.

FIG. 25 is a cross section drawing of a small blood vessel 2300branching off a larger vessel 2305. The small blood vessel 2300 may betortuous as shown, but does not hinder the walking travel such as thatof a magnetic rod 2310 shown approaching clot 2315, which might be aclot in a brain or otherwise. Accordingly, the systems and methodsdescribed herein advantageously facilitate movement of magneticnanoparticles, and treatment of fluid obstructions, within tortuous orcurved vasculature (such as the neurovasculature). Such small clots 2315can be scrubbed as described for other, generally larger vessels such as2255 in FIG. 24 above. The scrubbing can be generated to remove piecesof occluding material with the appropriate field and gradient choices.These removed particles may be up to a few microns in size, and may notcause further downstream damage. In accordance with several embodiments,an advantage of this method of clearing a clot such as clot 2315 is thatthe occlusion might be total and difficult to reach by conventionalexisting methods, but the external rotating field provided by thesystems and methods described herein can walk the rods to the occlusionpoint. The thrombolytic drug may then be introduced, if possible, at thesite of the clot 2315. At that point, the stirring activity of themagnetic rods 2310 can make the drug interact with the clot 2315 muchfaster than a static delivery.

Although magnetic nanoparticles are sufficient to gently clear delicatestructures, it may sometimes be desirable to rapidly remove materialquickly, as is the case for ischemic stroke, in which parts of the brainare starved of blood. The same principles used with magneticnanoparticles may be employed with larger magnetic structures which arespecifically designed to rapidly remove occlusions by mechanicalabrasion while simultaneously increasing the flow of thrombolytic drugsto the blockage. These larger magnetic structures, termed here asthrombectomy devices, may be spheres with an abrasive material bonded onthe surface. They can be sub-millimeter in size up to a millimeter ormore, with the consideration that removal after the particular procedureis desirable, in some embodiments. This technique can result in smallerresidual emboli than is typically seen with conventional techniques. Afurther advantage of this method over existing procedures is thecontrollable magnetic character of the removed material. Thethrombectomy device, which is depicted herein as a sphere with amagnetic moment (i.e., a “magnetic ball”), may be tethered to simplifyretrieval of the device. In some embodiments, the thrombectomy devicecan be recovered in a manner similar to that proposed for the magneticnanoparticles, namely, the use of a magnetically-tipped guide wire. Theball's surface may comprise any one or a combination of the following:(i) contrast agent or agents which allow visualization with magneticresonance imaging, X-ray, PET, ultrasound technologies, or other imagingmodalities; (ii) drugs which accelerate destruction of the blockage;(iii) surface geometries designed and/or optimized to accelerategrinding; and (iv) abrasive surfaces to accelerate grinding.

FIG. 26A illustrates elements of the basic operation of themagnetically-enabled thrombectomy device, according to one embodiment,which is presented as a sphere 2430. The ball 2430 possesses a permanentmagnetic moment with South 2410 and North 2420 ends. An externallyapplied magnetic field 2450 which advances in the counter-clockwisedirection 2440 causes the ball to rotate. If the magnetic gradient isabsent, as is the case in FIG. 26A, no traction is generated against thesurface 2460 and the ball does not translate.

FIG. 26B depicts the same case as FIG. 26A except that a magneticgradient 2480 is present in a substantially fixed direction 2480 whichgenerates a force in the direction 2480 acting on the magnetic ball 2430to press it against the vessel wall 2460. As a result, traction iscreated and translational motion occurs in direction 2470 with thecounter clockwise rotation 2440 of the field.

An example application of this technique is described as follows. FIG.27A is a cross section view of a blood vessel 2510, totally occluded,with no blood flow. As shown, a magnetic ball 2530 can stir the regionjust proximal to occlusion 2515 while mechanically grinding theocclusion's surface 2522. Contact against surface 2522 is created by agradient in direction 2520 which results in a translational force indirection 2520. Clockwise motion of magnetic ball 2530 causescirculation pattern 2525 to be formed, which accelerates action of thethrombolytic drug.

In the cross section view of FIG. 27B, the rotational interaction inblood vessel 2510 has continued and ball 2530 has deeper penetrationinto occlusion 2515 in the translation direction 2520.

In FIG. 27C, the rotating magnetically-enabled ball 2530 has opened ablocked channel 2535 in vessel 2510, leaving minor remains of occlusionmaterial. In some embodiments, the principal mechanism for removal ofthe occlusion 2515 is not the abrasion of the magnetic ball 2530 againstthe occlusion 2515, but is the increased exposure of the occlusion to atherapeutic agent (e.g., thrombolytic drug). In some embodiments, theprincipal mechanism for removal of the occlusion 2515 is not due tohyperthermia caused by inductive heating of the magnetic ball 2530arising from a time-varying magnetic field. In some embodiments, themagnetic ball 2530 does not have an abrasive coating.

FIG. 27D shows a means of capture and removal of themagnetically-enabled ball 2530 from the vessel 2510. The external field2520 is no longer rotated or is removed, which causes the ball 2530 tono longer translate to the right. At an appropriate time, beforerestored blood flow has pushed the magnetically-enabled ball 2530downstream, a magnet-tipped probe 2540 is inserted and captures ball2530 for removal by retracting magnet-tipped probe 2540.

Cross sectional view FIG. 28A shows a tethered magnetically-enabled ball2610 in vessel 2605. The tether 2630 allows the ball 2610 to rotate withthe magnetic field, using attachments to be shown in FIGS. 28B or 28C.In FIG. 28A, the North 2640 and South 2645 ends of the magnet aredepicted at the ends of the black arrow. A free rotation of the magneticfield 2640-2645 allows grinding of the thrombus or plaque material 2620inside of the vessel 2605. The tether 2630 ensures the magnet 2610 canbe manually retrieved without the need of the magnetically-tipped wire2540 that was depicted in FIG. 27D. In accordance with severalembodiments, tether 2630 will not wind on the ball 2610 under rotation(for example, when designed according to methods and devices of FIGS.28B and 28C).

FIG. 28B shows a first embodiment of a tether 2660 which allows rotationaround a rotational axis 2650 of magnetic ball 2610. As shown in FIG.28B, a tether end 2665 is inserted through the rotational axis 2650loosely to ensure free rotation about the rotational axis 2650. North2640 and South 2645 arrow depicts the magnetization direction of ball2610.

FIG. 28C shows a second embodiment of a tether. Tether 2670 allowsrotation around the rotational axis 2650 of the magnetic ball 2610(perpendicular to a loop 2675). As shown in FIG. 28C, the tethercomprises a loop 2675 which loosely surrounds the magnetic ball'srotational axis 2650 to ensure free rotation about the rotational axis2650. The North 2640 and South 2645 ends of arrow 2680 depict themagnetization direction of ball 2610.

The technologies described herein also may be used in removingvulnerable plaque 2715 on a vessel 2705 wall, as depicted, for example,in FIG. 29. In FIG. 29, a cross section view of a blood vessel 2705 isshown with vulnerable plaque 2715 on the top and bottom of the vessel2705. A rotating magnetic ball 2710 is shown grinding the plaque 2715 ina manner similar to that used on the occlusion 2515 depicted in FIG. 27Cand the tethered embodiment in FIG. 28A. This is made possible by usingan externally-generated magnetic gradient 2720 to direct the actionupwards towards the plaque 2715. In some embodiments, therapeutic agents(e.g., thrombolytic drugs) may also be present to substantially dissolvethe removed (e.g., ejected) plaque material.

To image the magnetic nanoparticles and magnetically-enabledthrombectomy device with modern imaging technologies, the particles canpossess a coating which makes them substantially opaque to that imagingtechnology. Example contrast coatings include contrast coatingsdetectable by x-ray, PET, MR and ultrasound imaging technologies. Suchcoatings can advantageously provide the ability to reconstruct a vesselwhich would normally be invisible due to the lack of blood flow in thatregion. Likewise, the ability to control and recollect the magneticnanoparticles can result in less toxic side effects, which may resultfrom use of traditional contrast agents. For example, X-ray contrastagents typically require multiple injections because they are swept awaywith blood flow and are not able to travel in high concentrations downlow-flow vessels (e.g., less than 1 cm/sec).

FIG. 30A is a cross section drawing of a small blood vessel 2820branching off a larger vessel 2810. The small vessel 2820 may betortuous, as shown, but does not hinder the walking travel of magneticrod collection and/or the rolling motion of a magnetically-enabled ball.Both technologies are schematically depicted as starting at the rightside of the small vessel 2825 and approaching a blockage 2815. Atsubsequent points in time, the location of the magnetic ball or magnetrod collection 2825 is identified at the points indicated by 2826, 2827,2828, and 2829. The translation direction of the magnetic rod collectionor magnetically-enabled ball is indicated by the arrow 2830 extendingfrom the body.

FIG. 30B is the same cross section drawing depicted in FIG. 30A. In thisview, the imaged locations of the magnetic rod collection or themagnetically-enabled ball are connected, thereby allowing a computer toreconstruct the path 2835 traveled. This path can be referenced againstpreoperative images to confirm the anatomy and to plan procedures usingnavigation along the path 2835.

Compositions for Use in the System

Various formulations of magnetic nanoparticles, whether formulated incombination with pharmaceutical compositions or not, may be used foradministration to a patient. Those of skill in the art will recognizehow to formulate various therapeutic agents (e.g., pharmaceuticalcompositions, drugs and compounds) for co-administration with themagnetic nanoparticles hereof, or administration separate from thenanoparticles. In some embodiments, various formulations of the magneticnanoparticles thereof may be administered neat (e.g., pure, unmixed, orundiluted). In some embodiments, various formulations and apharmaceutically acceptable carrier can be administered, and may be invarious formulations. For example, a pharmaceutically acceptable carriercan give form or consistency, or act as a diluent. Suitable excipientsinclude but are not limited to stabilizing agents, wetting andemulsifying agents, salts for varying osmolarity, encapsulating agents,buffers, and skin penetration enhancers. Example excipients, as well asformulations for parenteral and non-parenteral drug delivery, are setforth in Remington, The Science and Practice of Pharmacy 20th Ed. MackPublishing (2000) the disclosure of which is hereby expresslyincorporated by reference herein.

Some embodiments of magnetic nanoparticles can be formulated with acoating that is non-specialized toward any particular therapeutic agent(e.g., chemical or pharmaceutical composition). In some embodiments, thecoating could absorb a wide variety of therapeutic agents. The coatingcan be formulated to be thin, as well, so as to not substantiallyinterfere with the mutual interaction of the magnetic nanoparticles. Asa result, chemicals can be delivered in a more efficient way, reducingthe dose, cost, and dose-dependent side effects.

Magnetic nanoparticles with the non-specialized coating could beacquired and mixed with an operator-selected agent prior to injectioninto a subject. Thus, the operator can select a suitable agent for theparticular application. The devices used to attach a therapeutic agent(e.g., a chemical, a thrombolytic drug) to the magnetic nanoparticlescan include a traditional vortex mixer, ultrasonic mixer, a device whichmanipulates a magnetic field to result in dispersing the particles andmixing them with the chosen therapeutic agent, or other suitable mixingdevice. Operator-selected agents can include, for example, coatingswhich enhance the behavior of the nanoparticles in blood by making themeither hydrophilic or hydrophobic; coatings which buffer thenanoparticles and which optimize the magnetic interaction and behaviorof the magnetic nanoparticles; contrast agent or agents which allowvisualization with magnetic resonance imaging, X-ray, Positron EmissionTomography (PET), or ultrasound technologies (e.g., magnetodendrimers);drugs which accelerate destruction of a circulatory system blockage;tissue plasminogen activators (tPA), plasminogen, streptokinase,urokinase, recombinant tissue plasminogen activators (rtPA), alteplase,reteplase, tenecteplase, other drugs, or any combination of these.Coating magnetic nanoparticles with a non-specialized coating can haveadvantages. For example, magnetic nanoparticles can be injected withouttPA or other such drugs attached, but the nanoparticles can be used toconcentrate drugs which are introduced separately through the use offluid currents. In this way, the drugs can be more effective due to theability of the nanoparticles to concentrate the dose at the targetedlocation or therapeutic target. In some embodiments, such a process canreduce the effective dosage required by two or three orders ofmagnitude, saving in cost and possible deleterious drug side-effects. Insome embodiments, the magnetic nanoparticles can include a specializedcoating to facilitate bonding or attachment of a particular therapeuticagent. In some embodiments, the coating comprises a DNA coating coded toattract a particular therapeutic agent (e.g., by covalent linkages or bynoncovalent bonding or physical interactions). The DNA coating may bemodified with one or multiple thiol groups or other structures tofacilitate bonding or attachment.

In some embodiments, the surface of the coating (e.g., polyethyleneglycol coating) of the magnetic nanoparticles includes amino or hydroxylfunctional groups to which the therapeutic agents or diagnostic markersmay be covalently linked or conjugated. In some embodiments, linkagegroups such as iodoacetyls, maleimides or pyridyl disulfide mayfacilitate attachment. Physical interactions (e.g., electrostaticinteractions, hydrophobic/hydrophilic interactions, and affinityinteractions) may also be used to facilitate attachment of thetherapeutic agents or diagnostic markers to the magnetic nanoparticles.In some embodiments, therapeutic agents are loaded with iron oxidenanoparticles within the coating material (e.g., magnetoliposomes).

In some embodiments, the coating comprises a liposomal coating and oneor more therapeutic or diagnostic agents may be provided within or onthe coating. The liposomal coating may be configured to dissolve after aperiod of time, thereby preventing release of the agent until it reachesa target site. In some embodiments, the therapeutic agent may be coveredwith inert materials to prevent delivery prior to reaching a targetsite.

The magnetic nanoparticles can be biologically inert and not able to bemetabolized. In some embodiments, the coating comprises a polyethyleneglycol (PEG) coating, a polylactic acid (PLA) coating, apolylactic-co-glycolic acid (PLGA) coating, a polyvinyl acetate (PVA)coating, a dextran coating, and/or an oleic acid coating. The coatingcan advantageously remove a charge of the magnetic nanoparticle andprevent or reduce the likelihood of hemolysis. The coating can serve asa platform or scaffolding for attachment of therapeutic agents. In someembodiments, the coating includes an intermediate coating (e.g., an acidcoating) to facilitate attachment of a therapeutic agent. In someembodiments, the coating can be modified to include an acid layer tofacilitate conjugation or bonding of therapeutic agents to the coating.The coating may be layered in some embodiments, and optionally providecontrolled time release.

In some embodiments, the magnetic nanoparticles described herein can beused in purifying biomolecules through magnetic bioseparation. Forexample, by oscillating a magnetic field, magnetic nanoparticles canenhance a process of purifying biomolecules. In some embodiments, thesurface of the magnetic nanoparticles can be functionalized to attachdesired molecules. For example, diagnostic markers for various diseasessuch as cancer can be attached to the magnetic nanoparticles foroncology diagnosis and/or treatment applications. In some embodiments,nanoparticles coated with proteins can attach to damaged portions ofarteries to facilitate delivery of therapeutic agents to the damagedportions. The magnetic nanoparticles can be used to enhance magneticresonance imaging or other contrast agents to improve MRI or otherimaging results. In several embodiments, the magnetic nanoparticles canbe used as vectors for drug delivery by attaching drugs to the surfaceof the particles and directing them to a site (e.g., an area ofinflammation, a specific organ or specific cells). In accordance withseveral embodiments, the magnetic nanoparticles can be directed to asite to deliver a critical concentration of material with a therapeuticagent attached to the nanoparticles to the site. In some embodiments,the magnetic nanoparticles can be used to facilitate delivery ofvaccines.

In various embodiments, drug delivery to tumors or other canceroustissue or areas of inflammation can be facilitated with or withoutattaching the agents (e.g., anticancer or antineoplastic agents such asdoxorubicin, altretamine, asparaginase, bleomycin, busulfan,carboplatin, carmustine, chlorambucil, cisplatin, cladribine,cyclophosphamide, cytarabine, dacarbazine, diethylstilbestrol, ethinylestradiol, etopopside, mitomycin, mitotane, mitoxantrone, paclitaxel,pentastatin, pipobroman, plicamycin, prednisone, procarbazine,streptozocin, tamoxifen, teniposide, vinblastine, vincristine,chemotherapy agents or gene therapy agents) to the magneticnanoparticles described herein. Different types of molecules can beattached to the same magnetic nanoparticle or to different groups ofmagnetic nanoparticles (e.g., cancer-recognition agents andcancer-treating agents). In some embodiments, therapeutic agents can beattached to the magnetic nanoparticles to facilitate delivery across theblood-brain barrier for treatment of brain tumors or other diseasesinvolving the blood-brain barrier (e.g., meningitis, brain abscess,epilepsy, multiple sclerosis, neuromyelitis optica, neurologicaltypanosomiasis, progressive multifocal leukoencephalopathy, De Vivodisease, Alzheimer's disease, encephalitis, rabies) and other diseasesor neurodegenerative disorders of the central nervous system (e.g.,dementia, Parkinson's Disease and amyotrophic lateral sclerosis). Thetherapeutic agents may target bacteria, viruses, pathogens, or othermicroorganisms. In some embodiments, the magnetic nanoparticles could beused to carry out multiple different tasks in a particular sequence.

Therapeutic agents to treat brain tumors in combination with magneticnanoparticles delivered across the blood-brain barrier may include, forexample, bevacizumab or everolimus, procarbazine, carmustine, lomustine,irinotecan, temozolomide, cisplatin, methotrexate, etoposide,cyclophosphamide, ifosfamide and/or vincristine. Hyperthermia may alsobe delivered using the magnetic nanoparticles by subjecting the magneticnanoparticles to an alternating magnetic field, thereby producing heat.Therapeutic agents to treat Alzheimer's Disease in combination withmagnetic nanoparticles may include, for example, cholinesteraseinhibitors and/or memantine. Therapeutic agents to treat meningitis incombination with magnetic nanoparticles may include, for example,metronidazole. Therapeutic agents to treat epilepsy in combination withmagnetic nanoparticles may include, for example, amytal, amobarbital,fosphenytoin, and/or leveteracitam. Gene therapy may also be used inconjunction with magnetic nanoparticles to treat, for example, leukemia,myeloma, Parkinson's disease and other diseases or disorders. Viral ornon-viral methods may be used as vectors in the gene therapy.

Therapeutic agents to treat arteriovenous malformations or hemorrhagesor to facilitate embolization of tumors in combination with magneticnanoparticles may include agents that promote anti-angiogenesis toinduce formation of thrombus or embolus material. Hyperthermia may alsobe delivered using the magnetic nanoparticles (e.g., by subjecting themagnetic nanoparticles to an alternating magnetic field, therebyproducing heat).

Synthesizing Magnetic Nanoparticles

In some embodiments, a method for synthesizing magnetic nanoparticles(e.g., iron oxide nanoparticles) includes aging ferrous hydroxide gelsat elevated temperatures, as described by Sugimoto and Matijevic in“Formation of Uniform Spherical Magnetite Particles by Crystallizationfrom Ferrous Hydroxide Gels,” Journal of Colloid and Interface Science,Vol. 74, No. 1, March 1980, which is expressly incorporated by referencein its entirety herein. In some embodiments, a method for synthesizingiron oxide nanoparticles includes precipitation of precursor ferroushydroxide (Fe(OH)₂), aging the precursor with excess ferrous sulfate(FeSO₄), and laundering and collection of the final product. In someembodiments, the process involves a seeded crystal growth process.

In some embodiments, the method includes precipitation of an iron(hydrous) oxide precursor from FeSO₄(aq) solution reacted with potassiumhydroxide and potassium nitrate. The iron source, potassium hydroxide,and potassium nitrate can be added to a container at a firsttemperature, such as room temperature, and then heated to produce areaction or the ingredients can be added to a container with a liquidthat is at an elevated temperature, such as boiling water. The boilingwater can act as a stirring mechanism for the ingredients added afterboiling. This can offer a better control of the reaction and give a moreuniform and narrow particle size distribution. The method can beperformed with or without stirring the ingredients. The reaction in themethod can be performed at 85° C., 90° C., 95° C., 100° C., or anothertemperature sufficient to cause the reaction. The method can includeprecipitating an iron sulfate aqueous solution with potassium hydroxide(KOH). The precursor iron (hydrous) oxide can be mixed with an excess ofFeSO₄(aq) to produce substantially phase pure magnetite particulate. Insome embodiments, a polymer or other coating substance is used to coatthe nanoparticles. The polymer can be added to the solution prior toadding the iron source such that the polymer completely or partiallydissolves in the solution before formation of nanoparticles commences orafter adding the iron source. The polymer can be polyethylene glycol1450 (e.g., PEG-6 or PEG-32). The method can include washing theparticulate with de-ionized water until a substantially constantspecific conductivity in the supernatant is achieved. The washing stepcan be followed by one, two, three, or more than three additionallaundering cycles. In some embodiments, the process described herein canproduce a relatively large number of magnetic nanoparticles whilemaintaining control of the nanoparticle size distribution.

In some embodiments, iron oxide (e.g., magnetite) powders are producedhaving diameters greater than or equal to about 20 nm and/or less thanor equal to about 250 nm, greater than or equal to about 50 nm and/orless than or equal to about 150 nm, or greater than or equal to about 75nm and/or less than or equal to about 125 nm. The iron oxide powders canbe produced such that the magnetic susceptibility of the material isgreater than or equal to about 10 emu/g of powder, greater than or equalto about 20 emu/g of powder, greater than or equal to about 30 emu/g ofpowder, greater than or equal to about 40 emu/g of powder, greater thanor equal to about 50 emu/g of powder, greater than or equal to about 60emu/g of powder, greater than or equal to about 75 emu/g of powder,greater than or equal to about 100 emu/g of powder, greater than orequal to about 150 emu/g of powder, and/or greater than or equal toabout 200 emu/g of powder. In some embodiments, the iron oxide materialcan be provided in a phosphate buffered saline suspension at a solidscontent of greater than or equal to about 15 mg/mL and/or less than orequal to about 45 mg/mL, greater than or equal to about 20 mg/mL and/orless than or equal to about 40 mg/mL, greater than or equal to about 25mg/mL and/or less than or equal to about 35 mg/mL, or greater than orequal to about 28 mg/mL and/or less than or equal to about 31 mg/mL. Insome embodiments, the iron oxide powder can be provided in a phosphatebuffered saline suspension with a concentration of polyethylene glycolat a molecular weight of greater than or equal to about 1300 Da and/orless than or equal to about 1600 Da, greater than or equal to about 1350Da and/or less than or equal to about 1550 Da, greater than or equal toabout 1400 Da and/or less than or equal to about 1500 Da, or greaterthan or equal to about 1420 Da and/or less than or equal to about 1480Da.

In some embodiments, the composition of the synthesized particles,excluding coatings, is greater than or equal to about 85% iron oxide,greater than or equal to about 90% iron oxide, greater than or equal toabout 95% iron oxide, greater than or equal to about 99% iron oxide,greater than or equal to about 99.5% iron oxide, or greater than orequal to about 99.8% iron oxide. The iron oxide can comprise mixedphases and can be Fe₃O₄ and/or Fe₂O₃. In some embodiments, theimpurities from heavy metals (e.g., arsenic, mercury, lead, cadmium,bismuth, etc.) are less than or equal to about 300 ppm, less than orequal to about 250 ppm, less than or equal to about 200 ppm, less thanor equal to about 150 ppm, less than or equal to about 100 ppm, lessthan or equal to about 75 ppm, or less than or equal to about 50 ppm.Impurities can be determined using Inductively Coupled Plasma or othersimilar analytic techniques. In one embodiment, the magneticnanoparticles can include a Dextran coating, for example Dextran T1,Dextran T5, Dextran T10, Dextran T25, or Dextran T40. In someembodiments, the total viable count of microorganisms in the magneticnanoparticle material is less than or equal to about 200 colony-formingunits (cfu)/g, less than or equal to about 150 cfu/g, less than or equalto about 125 cfu/g, or less than or equal to about 100 cfu/g. In someembodiments, the content of yeast and/or mold in the magneticnanoparticles is less than or equal to about 200 cfu/g, less than orequal to about 150 cfu/g, less than or equal to about 125 cfu/g, or lessthan or equal to about 100 cfu/g.

In some embodiments, the materials used to manufacture the magneticnanoparticles include iron (II) sulfate heptahydrate having a puritythat is greater than or equal to about 90%, greater than or equal toabout 95%, greater than or equal to about 98%, or greater than or equalto about 99%. The materials can include potassium nitrate in the form offine crystals having a purity that is greater than or equal to about95%, greater than or equal to about 98%, greater than or equal to about99%, or greater than or equal to about 99.8%. The materials can includepotassium hydroxide having a purity that is greater than or equal toabout 75%, greater than or equal to about 80%, greater than or equal toabout 85%, or greater than or equal to about 87.9%. The materials caninclude pre-purified nitrogen. The materials can include polyethyleneglycol 1450 (e.g., PEG-6 or PEG-32) having a LOI residue that is lessthan or equal to about 2%, less than or equal to about 1%, less than orequal to about 0.5%, or less than or equal to about 0.1%. Thepolyethylene glycol can include impurities from heavy metals where theimpurities constitute less than or equal to about 100 ppm, less than orequal to about 50 ppm, less than or equal to about 10 ppm, or less thanor equal to about 5 ppm. The materials can include nano-pure reverseosmosis water.

As a result, magnetic nanoparticles can be formed having amono-crystalline core with diameters greater than or equal to about 20nm and/or less than or equal to about 200 nm, diameters greater than orequal to about 50 nm and/or less than or equal to about 100 nm, ordiameters greater than or equal to about 60 nm and/or less than or equalto about 80 nm, overlapping ranges thereof, diameters less than or equalto 170 nm, or diameters of any integer between about 20 nm and about 200nm. The mono-crystalline core can be advantageous because the structureallows for stronger magnetic interactions when compared with magneticparticles of similar sizes having poly-crystalline cores. Suchnanoparticles having reduced magnetic effects can be advantageous foruse in imaging applications, such as using them as contrast agents inMRI. The mono-crystalline magnetic nanoparticles described herein canalso include a coating of polyethylene glycol (PEG) which can serve as aplatform for attaching other drugs.

Administration of Magnetic Nanoparticles

In some embodiments, the magnetic nanoparticles are formulated foradministration by injection (e.g., intraperitoneally, intravenously,intraarterially, subcutaneously, intramuscularly, etc.), although otherforms of administration (e.g., oral, mucosal, etc.) can also be useddepending on the circulatory system blockage or other therapeutic targetto be treated. Accordingly, the formulations can be combined withpharmaceutically acceptable vehicles such as saline, Ringer's solution,dextrose solution, and the like. The particular dosage regimen (e.g.,dose, timing and repetition) may depend on the particular individual,that individual's medical history, and the circulatory system blockageto be treated. Generally, any of the following doses may be used: a doseof about 1 mg/kg body weight; at least about 750 pg/kg body weight; atleast about 500 pg/kg body weight; at least about 250 pg/kg body weight;at least about 100 pg/kg body weight; at least about 50 pg/kg bodyweight; at least about 10 pg/kg body weight; at least about 1 pg/kg bodyweight, or less, is administered. Empirical considerations, such as thehalf-life of a thrombolytic drug or the distance to a targeted locationfrom the main arterial blood flow, generally will contribute todetermination of the dosage.

In accordance with several embodiments, systems and methods are providedfor delivering non-dispersible or difficult to disperse agents (such asembodiments of the magnetic nanoparticles described herein).Administering magnetic nanoparticles by injection can present challengeswhere a substantially consistent infusion mass is desired as a functionof time. The infusion mechanism can include syringes, drip bags,reservoirs, tubing, drip chambers, other mechanisms, or any combinationof these. Magnetic particles can be dispersed in solutions such as, forexample, saline, Ringer's solution, dextrose solution, and the like.After a certain amount of time has elapsed in such solutions, magneticparticles can settle near the bottom of the solution due primarily togravitational forces on the particles possibly resulting in aninconsistent infusion mass.

For example, in certain applications, the magnetic nanoparticles aresupplied in a single-dose vial containing about 500 mg of magneticnanoparticles dispersed in about 17 mL of phosphate buffered saline(PBS), and are designed to be infused over the course of about an hour.These magnetic nanoparticles can settle out of dispersion in about 5 to10 minutes. Thus, the magnetic nanoparticles would settle faster thanthe time used to administer them, thereby causing the infusion mass tobe inconsistent.

Some embodiments of the magnetic nanoparticles described herein arenon-dispersible or difficult to disperse in a fluid. Some embodiments ofthe magnetic nanoparticles described herein include amagnetically-strong, relatively large, single-crystalline core having adiameter greater than or equal to about 50 nm and/or less than or equalto about 200 nm. The magnetic nanoparticles can also be coated with arelatively thin polyethylene glycol coating (e.g., less than or equal toabout 5 nm, 10 nm, 20 nm, etc.) to reduce the charge associated with theparticles. To disperse such nanoparticles in a fluid, e.g. saline, thethickness of the nanoparticle coating can be substantially increasedand/or the viscosity of the dispersion medium can be increased. In someembodiments, systems and methods are provided for maintaining asubstantially consistent infusion mass without altering the thickness ofthe nanoparticle coating or the viscosity of the dispersion medium.

In some embodiments, magnetic particles are made more dispersible bycoating the particles with a relatively thick coating. As an example, arelatively thick coating can be applied to magnetic nanoparticles toensure the nanoparticles remain in steric repulsion, such as magnetiteor hematite nanoparticles coated with Dextran or polyethylene glycolsurrounding a relatively small polycrystalline, magnetic core (e.g., themagnetic core has a diameter less than or equal to about 20 nm). In someembodiments, systems and methods for maintaining a consistent infusionmass can infuse magnetically strong particles without a relatively thickcoating, e.g., magnetic nanoparticles described herein having asingle-crystalline core with a diameter greater than or equal to about20 nm and/or less than or equal to about 200 nm.

Typically, magnetic particles experience steric repulsion because theyhave a relatively thick coating such that they remain substantiallydispersed throughout the infusion process. In some applications,magnetic particles are coated with a coating to reduce the magneticsusceptibility of the particles, like when the magnetic particles areused as contrast agents for use in magnetic resonance imaging. In someapplications, magnetic particles are coated with biodegradablesubstances, hydrophobic drugs, or other such coatings. Such coatings canbe effective in increasing the dispersion of the particles in asolution. In some embodiments, the magnetic nanoparticles describedherein and the infusion methods and systems described hereinadvantageously allow the magnetic nanoparticles to substantially remainin dispersion throughout an infusion process without experiencing stericrepulsion and/or without requiring a relatively thick coating.

In accordance with several embodiments, dispersion of the magneticnanoparticles is at least partially maintained through the use ofmicro-bore tubing. Micro-bore tubing can be provided in the infusionmechanism to keep particles entrained in the infusate during theinfusion process. Typical infusion sets include tubing having an innerdiameter of about 4 mm. By decreasing the diameter of the tubing,infusion velocity is increased for a given infusion rate. This increasein velocity can be sufficient to reduce the amount of particles thatsettle in the tubing of the infusion mechanism such that the infusionmass remains substantially consistent throughout the infusion process.For example, a micro-bore tubing can have an inner diameter of less thanor equal to about 0.05 inches, less than or equal to about 0.048 inches,less than or equal to about 0.034 inches, and/or less than or equal toabout 0.023 inches. The inner diameter can depend on the desired fluidvelocity through the tubing, the diameter of the particles to beinfused, the length of tubing desired, or any combination of these.

The micro-bore tubing can have a desired length and/or hold a desiredvolume of material. For example, the micro-bore tubing can be at leastabout 40 inches in length and/or less than or equal to about 180 inchesin length, it can be at least about 50 inches in length and/or less thanor equal to about 100 inches in length, or it can be at least about 57inches in length and/or less than or equal to about 61 inches in length.The micro-bore tubing can have a volume that is at least about 0.3 mLand/or less than or equal to about 2.0 mL, at least about 0.4 mL and/orless than or equal to about 1.8 mL, or at least about 0.5 mL and/or lessthan or equal to about 1.7 mL. The micro-bore tubing can be configuredto have a length and inner diameter configured to deliver a desiredamount of solution in a desired amount of time. For example, themicro-bore tubing can be configured to deliver about 68 mL in about 60minutes. In some embodiments, a micro-bore tubing having an innerdiameter of about 0.031 inches and a length of about 160 inches delivers68 mL of solution in about 57 minutes while keeping the magneticnanoparticles entrained. FIG. 31 illustrates an embodiment of aninfusion system 3100 having micro-bore tubing 3102 that is at leastpartially pre-filled with a particle dose that is administered (e.g.,pushed) to the patient with sterile saline 3104 from a syringe pump3106.

In some embodiments, the dispersion of the particles is at leastpartially maintained through the application of ultrasonic energy. FIG.32A illustrates an example of such a system 3200. The example system3200 includes a particle volume 3202 partially contained within areservoir 3204, inlet tubing 3206 from a syringe pump, outlet tubing3208 leading to a patient, and an ultrasonic transducer 3210 in contactwith the reservoir 3204. The ultrasonic transducer 3210 can produce atimed (e.g., periodic) ultrasonic pulse to maintain the dispersion inthe reservoir 3204. Infusion of the magnetic nanoparticles can be drivenby a saline infusion via a syringe and syringe pump (not shown). In someembodiments, the ultrasonic transducer 3210 delivers substantiallycontinuous ultrasonic energy to the reservoir 3204. In certainembodiments, the reservoir 3204 includes coiled infusion tubing (notshown) in a medium (e.g., a liquid or gel) configured to transmitultrasonic energy to the tubing. The system 3200 delivering theultrasonic energy can include, for example, ultrasonic transducers,ultrasonic pads, ultrasonic vibrators, ultrasonic stirrers, or anycombination of these. In some embodiments, the outlet tubing 3208, or aportion of the outlet tubing 3208, can be micro-bore tubing configuredto maintain dispersion of the particles upon delivery to the patient. Insome embodiments, as illustrated in FIG. 32B, the reservoir 3204 caninclude a diaphragm 3212 that reduces the internal volume for theparticle dispersion 3202 in response to increasing volume from thesyringe/syringe pump infusion.

In some embodiments, the dispersion of the magnetic nanoparticles is atleast partially maintained through the application of magnetic fields.FIG. 33 illustrates an example of a system 3300 having a reservoir 3304with a particle volume 3302, an inlet tube 3306 from a syringe, anoutlet tube 3308 to a patient, and at least one magnet 3310 configuredto produce a time-varying magnetic field. The magnetic nanoparticles canrespond to the time-varying magnetic field by moving within thedispersion 3302 to substantially maintain a consistent infusion mass.The one or more magnets 3310 can be permanent magnets configured torotate to produce a time-varying magnetic field. The one or more magnets3310 can be electromagnets that have varying currents induced throughthem to produce a time-varying magnetic field. The one or more magnets3310 can be any combination of permanent magnets and electromagnets. Insome embodiments, more than one rotating magnet 3310 is spaced aroundthe reservoir 3304, rotating in similar or different planes. Themagnetic field can vary with a frequency greater than or equal to about1 Hz and/or less than or equal to about 100 Hz, greater than or equal toabout 5 Hz and/or less than or equal to about 50 Hz, and/or greater thanor equal to about 10 Hz and/or less than or equal to about 30 Hz,greater than or equal to about 1 Hz and/or less than or equal to about10 Hz, or overlapping ranges thereof, less than 100 Hz, less than 50 Hz,less than 30 Hz, less than 10 Hz. In some embodiments, the outlet tubing3308, or a portion thereof, includes micro-bore tubing as describedherein with reference to FIG. 31. In certain embodiments, the reservoir3304 includes a diaphragm (not shown) that reduces the internal volumefor the particle dispersion 3302 in response to increasing volume fromthe syringe/syringe pump infusion, similar to the ultrasonic system 3200illustrated in FIG. 32B.

In some embodiments, the dispersion of the magnetic nanoparticles is atleast partially maintained through the application of mechanicalagitation. FIG. 34 illustrates an example of a system 3400 having a dripbag 3402, a support structure 3404 for supporting the drip bag 3402, anoutlet tube 3406 to the patient, and a mechanical agitator 3408 coupledto the drip bag 3402 and/or support structure 3404. In some embodiments,the system includes a drip chamber with a conical bottom (not shown)coupled to the drip bag 3402 and the outlet tube 3406 which allows auser to view and/or control flow into the outlet tube 3406. Thedispersion can be maintained by continuous or timed agitation of an IVinfusion drip bag 3402 through repeated squeezing of the drip bag 3402.In certain embodiments, the agitator 3408 comprises a mechanicallyactuated bar that squeezes a portion of the bag 3402 in a timed,continuous, periodic, and/or rhythmic manner. The mechanical agitation3408 can be repeated with a frequency greater than or equal to about 0.1Hz and/or less than or equal to about 5 Hz, or a frequency greater thanor equal to about 0.25 Hz and/or less than or equal to about 3 Hz, oroverlapping ranges thereof. In some embodiments, the agitator 3408 canbe an air bladder, or balloon, coupled to a compressor that pulses airto the bladder, pauses to allow the air from the bladder to bleed intothe drip bag 3402, and then repeats. In some embodiments, the agitator3408 can be a mechanical vortexer configured to mechanically agitate theparticle container. In some embodiments, the dispersion in the drip bag3402 can be maintained through any combination of mechanical agitation,ultrasonic energy, and magnetic energy as described herein. In someembodiments, the outlet tubing 3406, or a portion thereof, includesmicro-bore tubing as described herein with reference to FIG. 31.

In some embodiments, the infusion mass is delivered using multiple boluscartridges at timed intervals (e.g., periodic or randomized). FIG. 35illustrates an example embodiment of such an infusion system 3500. Thesystem 3500 includes an infusion pump 3502, multiple syringes 3504 orother delivery mechanisms, the syringes being coupled to amulti-connector or manifold 3506, the multi-connector or manifold 3506coupled to outlet tubing 3508. The multiple syringes 3504 can bepreloaded with individual doses and at least one syringe with saline3510 can be included to infuse (e.g., push) each dose down the outlettubing 3508 and/or flush the infusion line. In some embodiments,ultrasound and/or magnetic energy 3512 can be applied to the injectionpump 3502 to maintain dispersion in one or more syringes 3504. In someembodiments, the outlet tubing 3508, or a portion thereof, includesmicro-bore tubing such as described herein with reference to FIG. 31.

In some embodiments, the dispersion of the particles is at leastpartially maintained through the use of fluid dynamic mixing. FIG. 36Aillustrates an example of such a fluid dynamic mixing system 3600. Inthis example, the fluid dynamic mixing system 3600 includes continuouslymixing syringes 3602 wherein a first syringe 3602 b includes thedispersion 3604, a second syringe 3602 a is empty, and a third syringe3602 c includes a saline solution 3606. The syringes 3602 are fluidiclycoupled by a manifold 3608. The system 3600 includes a valve 3610controlling flow to an outlet tube 3612. The fluid dynamic mixing system3600 can have one or more saline valves 3614 to control the introductionof saline 3606 into the manifold 3602 and/or outlet tubing 3612. Thefluid dynamic mixing system 3600 can function by having the emptysyringe 3602 a withdraw at substantially the same time and/or rate asthe dispersion syringe 3602 b delivers, thereby transferring thedispersion 3604 from one syringe to the other in a substantiallycontinuous manner, as depicted in FIG. 36B. This substantiallycontinuous motion of the fluid can be sufficient to maintain thedispersion. At defined time intervals, a valve 3610 could open to allowthe appropriate volume of solution to be delivered to the subject, afterwhich the valve 3610 can close so that the mixing can continue. Thesaline syringe 3602 c can be included and used to flush the dispersant3604 from the tubing 3612 into the subject. In some embodiments, theoutlet tubing 3612, or a portion thereof, includes micro-bore tubingsuch as described herein with reference to FIG. 31.

Example Method of Operation

To illustrate an example method of operation, an example magnetomotivesystem and user interface will be described with reference to FIGS.46A-46G and FIGS. 47A and 47B, in accordance with embodiments of theinvention. The magnetomotive system and associated magnetic rotors canbe configured to enhance infusion of co-administered intravenous agentsinto selected low flow vessels (e.g., where flow is less than or equalto about 1 cm/s) located within an arterial or venous vessel. FIGS.46A-46B illustrate an embodiment of a user interface module 4600 for usewhen operating the magnetomotive system 4715 to control magnetic rotors(e.g., magnetic nanoparticles) to deliver a therapeutic agent (e.g., tPAor other thrombolytic agent) to a therapeutic target (e.g., thrombus orclot) in a patient's head (e.g., vessel providing blood flow to thebrain). The user interface module 4600 can be configured for use totreat other vessels or body structures of a patient as well.

The magnetomotive system can comprise any of the systems describedherein or components thereof (such as the systems of FIGS. 1-5). Forexample, the magnetomotive system 4715 can include a portable supportbase 4702 and an arm positioner 4712, as illustrated in FIG. 47. Thesystem 4715 can include a magnetic stator system configured to produce adesired magnetic field, such as those described herein with reference toFIGS. 1, 4, and 5. For example, a magnetic stator system can include aneodymium-iron-boron permanent magnet block connected to a shaft andyoke assembly. In some embodiments, the yoke assembly is machined usingcarbon fiber plates to decrease weight and improve performance.

The permanent magnet block can be a single permanent magnet or multiplemagnets. For example, the permanent magnet block can comprise two,three, four, six, eight, or some other number of NdBFe50medium-temperature 2 inch cubes. A mechanical drive train can connectthese assemblies to a pair of electric motors configured to vary inangulation and time to vary the magnetic field produced by the magneticblock. In some embodiments, the magnetic block can have a rotationalfrequency of at least about 1, 2 or 3 Hz and/or less than or equal toabout 10 Hz (e.g., 2-4 Hz, 1-5 Hz, etc.) to produce a desired varyingmagnetic field. In some embodiments, the magnetic block is configured toproduce a desired magnetic field at least about 6 inches from thesurface of the magnetic block. In some embodiments, the magnetic blockis configured to produce a magnetic field that is less than or equal toabout 5 Gauss at about 54.6 cm inches from the magnetic block, and/orless than or equal to about 1 Gauss at about 94 cm from the block. Inseveral embodiments, these mechanisms are housed in a protective coverthat protects the operator and patient from mechanical hazards, as wellas protects the elements and assemblies contained within the housingfrom hazards outside the housing.

The arm positioner 4712 can be configured to position and/or orient themagnetic stator system 4715 in a desired location, such as adjacent to apatient's head during treatment or into a stowed position when not inuse. The system 4715 can include mechanisms to substantially secure themagnetic stator system in a desired location, such as locking orfriction mechanisms. The system 4715 can advantageously include atouchscreen interface module 4600 configured to display information tothe operator and receive input from the operator for use in controllingthe system.

The magnetic rotors can be formed when a magnetic field manipulatesmagnetic nanoparticles to form larger structures. The magneticnanoparticles can be made of magnetite (Fe₃O₄) usingpharmaceutical-grade reagents by chemical precipitation of ferrouschloride under heat and pressure. After the magnetite core hascrystallized to approximately 100 nm, a thin coating (e.g., about 10 nm)of PEG 1450 can be adsorbed onto the surface of the core. In someembodiments, the magnetite particles are sterilized using gammaradiation or other sterilization techniques. In one embodiment, themagnetic nanoparticles are suspended in a sterile saline solution (e.g.,non-pyrogenic buffered saline (USP)) to be administered intravenouslyconcurrent with a therapeutic agent (e.g., as tPA or other thrombolyticdrug). In some embodiments, two IV sites are established, one foradministration of the therapeutic agent and one for the infusion ofmagnetic nanoparticles. In one embodiment, administration can includeabout 500 mg of particles in about 17 mL of saline solution, withparticle sizes ranging from about 50 nm to about 150 nm. In oneembodiment, the final concentration of magnetic nanoparticles is about29.4 mg/mL. An infusion rate of the magnetic nanoparticles can be lessthan or equal to about 0.33 mL/min (e.g., less than or equal to about0.30 mL/min, 0.25 mL/min, 0.20 mL/min, or 0.15 mL/min). The magneticnanoparticles can be administered with an infusion mass that is lessthan or equal to about 10 mg/kg (e.g., less than or equal to about 9mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg).

In one embodiment, the touchscreen interface module 4600 displays theuser interface 4601 illustrated in FIGS. 46A-46G. The user interfacemodule 4600 can aid in the proper operation of the system by allowing anoperator to enter appropriate information, display progress oftreatment, allow a user to manipulate the system, pause operation,modify operating parameters, and the like. For example, the userinterface 4601 can provide the operator the ability to select atherapeutic target or region by cranial hemisphere and major arterialvessel (or vessel branch). The user interface 4601 can displayinformation to the operator so the operator can verify the therapeutictarget, a status of the magnetic stator system, and a time remaining fortherapy delivery. In some embodiments, the therapeutic target or targetlocation is identified without requiring imaging or visualization of thetherapeutic target (e.g., without imaging of a clot). For example, thetherapeutic target may be identified based on measured blood flow orother indications of fluid obstruction.

As an example of using the system and user interface, a treatment of atherapeutic target in the patient's head will be described withreference to FIGS. 46A-46G and FIGS. 47A and 47B. Although oneembodiment of a magnetic control or stator system is referenced herein,the other magnetic control or stator systems described herein may alsobe used. The patient can be placed in a supine position with thepatient's head positioned using a securing system, such as a head rest4705, as shown for example, in FIG. 47B. The patient can be prepared toreceive the treatment according to standard protocols of the treatinginstitution. A magnet pod 4710 (which may include a rotatable permanentmagnet and the mechanical mechanisms to effect rotation of the permanentmagnet as described herein) of a magnetic control system 4715 can bepositioned adjacent to a side of the patient's head proximate to anaffected hemisphere, or the magnet pod 4710 can be positioned adjacentto the top or crown of the patient's head (as shown, for example, inFIG. 47B). In some embodiments, positioning the magnet pod 4710 of themagnetic control system 4715 adjacent to the top or crown of the headprovides advantageous alignment with vessels associated with blood flowto and/or from the brain and/or minimizes potential electromagneticinterference issues.

Positioning the magnet pod or block 4710 of the magnetic control orstator system 4715 can include using one or more mechanical features,e.g., the positioning assembly 4712 (which may be composed of multipleindependently controllable linkages or a single, unitary member) andportable support base 4702, to position and/or orient the magneticstator system 4715 in a desired location relative to the patient. Thepositioning assembly 2712 may include multiple pivots, joints, and/orhydraulic mechanisms that each can be adjusted individually or incombination. The positioning assembly 4712 can adjust the magnet pod4710 along multiple axes or without restriction (e.g., six degrees offreedom) in order to provide precise positioning with respect to a headangle of a patient. The positioning assembly 4712 may include lockingmechanisms to prevent movement once a desired orientation and positionis obtained. In some embodiments, the magnetic stator system 4715 can bepositioned perpendicular to the patient's head and level with thepatient's ear at a distance of between 2 and 20 cm (e.g., between 2 and6 cm, between 4 and 10 cm, between 6 and 12 cm, between 8 and 20 cm,overlapping ranges thereof, 8 cm, or any distance within the recitedranges) from the patient's head. As another example, the magnetic statorsystem 4715 can be positioned parallel with the patient's head andadjacent the top or crown of the patient's head, as shown for example inFIG. 47B. The magnetic stator system 4715 can be configured to besubstantially secured in place during use or it can be configured tomove during use through manual operation, automatic operation, or somecombination thereof. In some embodiments, the head rest 4705 can be usedto position the patient's head and to substantially secure it in a fixedlocation and/or orientation. The head rest 4705 can be disposable. Inone embodiment, the head rest 4705 has one side cut shorter than theother to facilitate alignment of the magnetic stator system 4715 withthe patient.

The operator can select an affected hemisphere of the head or brainwhich contains the therapeutic target (e.g., clot or other fluidblockage). In FIG. 46A, the operator can use the interface 4601 toselect the affected hemisphere through a hemisphere selection element4603 where the selection corresponds to a side of the head where therapyis to be delivered. In some embodiments, the user interface 4601presents two options in the hemisphere selection element 4603, a “LEFT”and a “RIGHT” option, with associated images 4605 a and 4605 b. Inresponse to the operator's selection, the head angle image 4607 canchange to reflect the selection.

In some embodiments, the operator selects a specific arterial branch totarget. In FIG. 46B, the operator can use the interface 4601 to select atargeted artery through an artery selection element 4609. The arteryselection element 4609 can include a list of arterial branches and theoperator can select the specific arterial branch to target. By touchingthe artery selection element 4609, a list of available selections 4611can be displayed. For example, the list of available selections 4611illustrated includes ACA (anterior cerebral artery), MCA (middlecerebral artery), MCA Anterior, MCA Posterior, MCA Proximal, ICA(proximal MCA/internal carotid), PCA/distal basilar (posterior cerebralartery/distal basilar). Upon selection, the image associated with thehead angle 4607 can show an arrow 4629 (shown in FIG. 46E) predicting adirection of infusion of the therapeutic agent.

In several embodiments, the operator sets or inputs a head angle of thepatient, where the head angle is the angle of the patient's headrelative to horizontal. The head angle of the patient can be changedduring treatment using the user interface 4601. In FIGS. 46C and 46D,the operator can use the interface 4601 to set the head angle of thepatient using a bar slider 4613, as illustrated in FIG. 46C, or bymanipulating the head angle image 4607, as illustrated in FIG. 46D.Dragging the slider 4614 changes the head angle of the patient from 0degrees to 90 degrees, where 90 degrees corresponds to when the patientis sitting up. Tapping above or below a current position of the slider4614 can increase or decrease the head angle value by a defined amount(e.g., 5 degrees, 10 degrees, 20 degrees). Tapping upper and lower boxes4615 a and 4615 b, respectively, can increase or decrease the head angleby 1 degree. As illustrated in FIG. 46D, the operator can drag a fingeror input device on the interface 4601 around the head angle image 4607to adjust the head angle.

In accordance with several embodiments, once the affected (e.g., target,hemisphere, targeted artery, and head angle are set, the operator canbegin the procedure. FIG. 46E illustrates a “Start Procedure” button4617. Before the affected hemisphere, targeted artery, and head angleare set, the button 4617 can be disabled and can indicate that it isdisabled through the use of color, text, or other indicator. In someembodiments, the button 4617 does not appear until the parameter inputsare entered. For example, the button 4617 can be grey before theselections above have been made and green after. By pressing the “StartProcedure” button 4617, the magnetic stator system can be activated, atwhich point particle infusion should begin.

In one embodiment, the duration of infusion is about 60 minutes. Invarious embodiments, the duration of infusion is between 5 minutes and120 minutes (e.g., between 5 minutes and 20 minutes, between 10 minutesand 30 minutes, between 15 minutes and 45 minutes, between 30 minutesand 60 minutes, between 45 minutes and 90 minutes, between 60 minutesand 120 minutes, overlapping ranges thereof, or any time duration withinthe recited ranges. In some embodiments, the system automaticallysuspends after a predetermined time (e.g., 90 minutes) has elapsed withthe magnetic stator system in an activated state, as indicated by thecountdown timer 4619. In accordance with several embodiments, themagnetic stator system continues to operate for a certain time period(e.g., about 30 minutes) after infusion is complete. As illustrated inFIG. 46F, when the operator presses the “Start Procedure” button 4617,it can be changed to or replaced by a “Stop Magnet” button 4621. Bypressing the “Stop Magnet” button 4621, the magnetic stator system canbe deactivated, the countdown timer 4619 can be paused, and the button4621 can change to or be replaced by a “Resume” button 4623, asillustrated in FIG. 46G. When the magnet has been stopped, the operatorcan adjust the head angle of the patient, reset the system by pressingthe reset button 4625, and/or exit the system by touching the exitbutton 4627. Pressing the “Resume” button 4623 can change it back to the“Stop Magnet” button 4621, in accordance with one embodiment.

As an example of a method of treatment of a clot using the magneticstator system and magnetic rotors, the magnetic stator system can bepositioned next to the head of the patient on the side of the affectedhemisphere or at the top of the crown of the head. Magneticnanoparticles and tPA can be infused concurrently through an IV or othermethod described herein (e.g., through micro-bore infusion tubing).Using a control system such as the control systems described herein, anoperator can use the magnetic stator system to magnetically manipulatethe magnetic nanoparticles to form magnetic rotors which act to createor increase blood flow currents directing the tPA to the clot. In thisway, the magnetic rotors can increase tPA diffusion and accelerate clotdestruction. The operator can control the magnetic stator system tocreate a desired varying magnetic field.

By alternating a rotational direction of the magnetic stator system, theoperator can direct the magnetic rotors within a vessel. For example,within a vessel, a velocity of blood increases with distance from thevessel wall, where the velocity is approximately zero. A clotted vesselbranch will obstruct fluid flow resulting in the velocity dropping tozero at the opening of the branch. Within such low velocity regions,magnetic nanoparticles generally assemble to be controlled by themagnetic stator system. When assembled, the magnetic stator system canagglomerate the magnetic nanoparticles into larger structures (e.g.,magnetic rotors having an oblong shape). With a varying magnetic field,the magnetic rotors can rotate, resulting in an end-over-end motion thatresults in the magnetic rotors traveling into or next to the blockedbranches. The resulting rotational motion of the magnetic rotors cancreate new currents or increase low-velocity currents. The resultingcurrents can concentrate a therapeutic agent in an otherwiseinaccessible or difficult to access region. By changing the rotation ofthe magnetic stator system, additional branches can be infused. Forexample, different rotational directions can result in the magneticrotors traveling to different branches. Rotational directions can bealternated to direct magnetic rotors to multiple branches. In accordancewith several embodiments, the magnetic rotors need not contact thetherapeutic target to treat (e.g., reduce, erode, lyse, degrade, clear,or otherwise address) the target. For example, the magnetic rotors canfacilitate treatment (e.g., removal, lysis or erosion) of a thrombus orclot without scraping or contacting the clot, or without the contactbeing the primary cause of action.

Having described embodiments of the magnetomotive stator system andmethods of controlling magnetic nanoparticles and other magnetic rods(e.g., magnetic tools), several advantages can be observed when comparedto devices and pharmaceutical compositions currently on the market.First, the ability to combine the magnetic gradient with the magneticfield in an advantageous way that allows for magnetic rotors to becontrolled from a distance, as opposed to catheters and cannulae whichmay cause unintended injury to a patient. Second, the ability toconstruct a compact mechanism that allows for the magnetic field to bechanged in time in a simple and precise way, as well as possiblyoptimized, so that control is enabled over the wireless rotors, is asignificant enhancement in view of pharmaceutical compositions that arehard to precisely control in vivo at normal dosages.

In addition, in one embodiment, when the magnetic rotors comprisemagnetic nanoparticles, such as magnetite or another ferromagneticmineral or iron oxide, the rotors can be manipulated in a way thatimproves mixing of a chemical or pharmaceutical agent that is in thevicinity of the magnetic nanoparticles. The use of the magnetic gradientcombined with a time-varying magnetic field allows for flow patterns tobe created which then amplifies the interaction of the chemical orpharmaceutical. This mechanism has been observed in animal models forthe destruction of clots within the endovascular system using tPA as athrombolytic. The pharmaceutical compositions can also be attached tothe magnetic nanoparticles to perform the same function. As a result,less of those agents may be used for patient treatment provided that thenanoparticles are able to be navigated to and interact with the desiredtargets using the magnetic gradient and the time-varying magnetic fieldof the system.

In various embodiments, clots or thrombi of sizes larger than can beeffectively treated by drug treatment (e.g., IV-tPA) alone can betreated more efficiently (e.g., faster and/or with improved lysis) withthe methods and systems described herein. For example, clots or thrombihaving a cross-sectional dimension of 8 mm, 9 mm, 10 mm or greater than10 mm (e.g., between 8 mm and 20 mm) can be effectively treated (e.g.,lysed, dissolved, removed). In various embodiments, use of the methodsand systems described herein can treat clots that have a near-zero orvery little likelihood of being lysed (e.g., recanalizing occludedvessels) using IV-tPA or other thrombolytic agent alone, such as clotsor thrombi having lengths greater than 8 mm.

The treatments described herein can be effective even for patientsdeemed to have no likelihood of recanalization based on CMR or NIHSSscores if tPA or other thrombolytic agent alone were to be administeredor patients suffering severe stroke as indicated by high NIHSS scores(e.g., greater than 5). In accordance with several embodiments, themagnetic nanoparticles do not aggravate tPA-induced hemorrhage.

In one embodiment, the magnetomotive system can make use of aneasy-to-understand user-interface which allows the user to control therotation plane of the magnetic field in a way that is not presentlyfound. In some embodiments, the user interface comprises a touchscreendisplay. Furthermore, imaging or other diagnostic technologies such asthose described herein can be incorporated into or used in combinationwith the user interface such that an operator can have real-timefeedback of the position of the magnetic nanoparticles, allowing fordynamic control and navigation. This can aid the operator to take stepsto increase the effectiveness of the process, for example, byintroducing more nanoparticles or more chemical agents. Images of thepatient and/or regions of interest can be incorporated into a userinterface to aid an operator, physician, technician, or the like to plana navigation route for the magnetic nanoparticles. Planning a navigationroute can comprise identifying a therapeutic target, such as a clot,choosing a practical injection site for the nanoparticles, and planninga route through the patient's vasculature to arrive at the targetedobject. In various embodiments, the injection site is in any artery orvein (e.g., arteries or veins in the hands, arms or legs, arteries orveins in the neck or shoulder area). Injection may also be performedsubcutaneously or intramuscularly. During the actual navigation of themagnetic nanoparticles, the operator can use the original images used toplan the navigation or the user interface can receive updated images toshow the operator, thus providing real-time imaging and feedback to theoperator. The real-time user-interface can be coupled with a single-axisor multi-axis robotic arm to allow the operator to substantiallycontinuously control the direction of nanoparticle infusion inreal-time. In some embodiments, treatment can be performed withoutrequiring actual imaging or visualization of the targeted object (e.g.,a clot).

As an example, the real-time user interface can incorporate imageinformation from an imaging system. The imaging system can be a systemincorporating one or more imaging modalities, configured to provideimaging data to the magnetomotive system. The imaging data can bederived from x-ray data, PET data, MR data, CT scan data, ultrasonicimaging data, or other imaging modality data. In some embodiments, themagnetic nanoparticles act as contrast agents in conjunction with animaging modality to facilitate identification of the location of themagnetic nanoparticles and/or to provide evidence of recanalization.

The magnetomotive system, in one embodiment, receives imaging data fromthe imaging system. In some embodiments, the imaging data comprisesinformation derived from an imaging modality that, in use, providesinformation about vasculature of a subject, relative position ofmagnetic nanoparticles, fluid flow, fluid obstructions, or anycombination of these. For example, the imaging system can produce imagedata based on ultrasound-based imaging. The imaging system can transmitsound waves aimed at an area of interest and interpret the echoed wavesto produce an image. The ultrasound-based imaging system can beconfigured to provide imaging data in real-time and can be configured toidentify fluid flow, tissue, liquid, magnetic nanoparticles, and thelike. In some embodiments, ultrasound-based diagnostic imaging ordetection is based on Doppler imaging or detection which providesinformation about fluid flow. For example, as described above,diagnostic ultrasound (e.g., Doppler ultrasound) can be tuned to therotational frequency of the rotating magnetic nanoparticle rods orrotors (e.g., 3 Hz). The feedback may be used to confirm location of themagnetic nanoparticles or to confirm recanalization has occurred. Anultrasound imaging system can image using frequencies from 1 and 18 MHz.The ultrasound images generated by the ultrasound-based imaging systemcan be two-dimensional, three-dimensional, or four-dimensional images.

The magnetomotive system, in one embodiment, registers a reference frameof the magnetomotive system to a reference frame of the imaging systemsuch that the imaging data from the imaging system is mapped topositions relative to the magnetomotive system. In some embodiments,registering the reference frames includes identifying elements of areceived image and mapping those elements to positions within a subject.In some embodiments, registering the reference frames includes receivinginformation about the image system itself such as a physical orientationof an imaging device relative to a subject, depth of scan or image,field of view, and the like such that the magnetomotive system can mapthe received image relative to a coordinate system of the magneticsystem. For example, an ultrasonic imaging system can send informationto the magnetomotive system about the frequencies transmitted into thetargeted area, the orientation of the imaging system relative to thesubject, the position of the imaging system relative to the patient, orany combination of these. As another example, a CT system can includeinformation about the depth of scan of an image, the field of view, theorientation of the system relative to the patient, and the like.

In one embodiment, the magnetomotive system identifies the magneticnanoparticles within the imaging data received from the imaging systemto track the particles, to navigate the particles, to switch betweencontrol modes (e.g. collection mode, vortexing mode, navigation mode,etc.), to monitor drug diffusion, or any combination of these.Identifying the magnetic nanoparticles can include analyzing the imagingdata for signals associated with magnetic nanoparticles. For example, inultrasonic imaging the magnetic nanoparticles can have a distinctivesignal in an image due to their motion, composition, position, behavior,orientation, or any combination of these. As another example, in PETsystems the magnetic nanoparticles can have a distinctive and/oridentifiable signal in an image based on attached contrast agents, thedensity or composition of the nanoparticles, the position of thenanoparticles, or the like.

The magnetomotive system can determine a position of the magneticnanoparticles relative to the magnetomotive system, based on theregistration of the reference frames. The magnetomotive system can plana navigation path from the identified position of the magneticnanoparticles to a desired location within the subject based on theimaging data from the imaging system. For example, the navigation pathcan include an acceptable path through the vasculature of the subjectfrom the current location of the magnetic nanoparticles to the targetedstructure, such as an occlusion. In some embodiments, planning anavigation path comprises identifying a therapeutic target, such as aclot, choosing a practical injection site for the nanoparticles, andplanning a route through the patient's vasculature to arrive at thetherapeutic target.

The magnetomotive system can manipulate a magnetic field produced by themagnetic system to navigate the magnetic nanoparticles according to thenavigation path. In some embodiments, manipulation of the magnetic fieldcauses the magnetic nanoparticles present within the vasculature toagglomerate into a plurality of magnetic nanoparticle rods and causesthe magnetic nanoparticle rods to travel through fluid within thevasculature by repeatedly walking end over end away from the magneticfield in response to rotation of the magnetic nanoparticle rods and themagnetic gradient and (b) flowing back through the fluid towards themagnetic field in response to the rotation of the magnetic nanoparticlerods and the magnetic gradient. In certain embodiments, the circulatingor oscillatory motion of the magnetic nanoparticles increases exposureof a targeted structure (e.g. a fluid obstruction) within a blood vesselof the vasculature to a therapeutic agent (e.g. a thrombolytic drug)present in the blood vessel and accelerates action of the therapeuticagent (e.g. the thrombolytic drug on the fluid obstruction). In someembodiments, the end over end motion creates a train of magneticnanoparticles which, in turn, creates a new fluid current. The new fluidcurrent can draw in the therapeutic agent and/or fresh body fluids.

The magnetomotive system can also be used to move nanoparticles withinsmall channels in a manner superior to approaches attempted withnon-varying magnetic fields. The combined use of the magnetic gradientwith a time-varying magnetic field allows for the nanoparticles totravel into small vessels, at which point therapy can be directed.

In some embodiments, the magnetic stator system alternates betweenclockwise and counter-clockwise rotation of the magnet to cause avortexing motion to improve the stirring or mixing action. In addition,the alternation between clockwise and counter-clockwise rotation canadvantageously facilitate infusion or recanalization of additionalbranches that are blocked or unreachable due to lack of or reduced bloodflow. For example, clockwise motion alone may not allow the magneticnanoparticles (e.g., magnetic rotors) to travel in an end-over-endmotion to certain branches. Alternating the rotational motionperiodically or in a controlled manner based on visualization orpre-obtained images can result in travel in opposite directions usingthe end-over-end motion, thereby accessing additional occluded branchesthat could not be reached by either clockwise or counter-clockwiserotation alone. In various embodiments, the rotational motion alternatesperiodically at a fixed frequency (e.g., every 5 seconds, every 10seconds, every 15 seconds, every 20 seconds, every 30 seconds, everyminute, every two minutes, every five minutes, every ten minutes, or anyother frequency). In some embodiments, the rotational motion isalternated to allow the magnetic nanoparticles to navigate or travelalong the vasculature from one occluded branch of a vessel to anotheroccluded branch depending on the anatomy of the vasculature.

EXAMPLES

Embodiments of the disclosure may be further understood in light of thefollowing examples of illustrative embodiments of methods and systems,which should not be construed as limiting the scope of the disclosure orclaims in any way. Moreover, the methods and procedures described in thefollowing examples, and in the above disclosure, need not be performedin the sequence presented

Example 1 Administration of Magnetic Nanoparticles to Rabbits

Anesthetized rabbits were used to create an endovascular obstructionmodel by using the jugular veins and generating a clot at this locationusing thrombin, a natural product that produces blood clots. Once astable clot was established, tPA (an enzyme commonly used to dissolveclots in endovascular obstruction patients), and magnetic nanoparticleswere directed to the clot location and the length of time to dissolvethe clot was recorded (See FIG. 38). After varying time points, theanimals were euthanized, the remaining clots were weighed and analyzedand tissues were collected to ensure that there was no damage to thevessel itself.

The endovascular obstruction model allows the determination whether themagnetomotive stator system can re-open a vein or artery faster thanwith tPA alone, and if the dosage of tPA can be reduced without causingdamage to the vein. The data gathered from the endovascular obstructionstudies clearly show that the magnetomotive stator system significantlyspeeds up the “clot-busting” activity of tPA.

Detailed Protocol

Summary: Deep Vein Thrombosis is a common and potentially deadlycondition, and current treatment options can do more harm than good insome cases. In one embodiment, an aim of the study is to use anon-survival anesthetized rabbit model of venous thrombosis to determinewhether we can substantially increase the efficiency of currentpharmacological treatment by manipulating commonly used MRI contrastmedia magnetically (Magnetic particles in imaging: D. Pouliquen et. al.,Iron Oxide Nanoparticles for use as an MRI contrast agent:Pharmacokinetics and metabolism; Magnetic Resonance Imaging Vol. 9, pp.275-283, 1991, the disclosures of which are hereby expresslyincorporated by reference herein).

Magnetics: The iron nanoparticles described above are currently used inhumans and considered safe.

Introduction: Deep Vein thrombosis (DVT) can be asymptomatic, but inmany cases the affected area is painful, swollen, red and engorged withsuperficial veins. Left untreated, complications can include tissuenecrosis and loss of function in the affected limb. A seriouscomplication is that the clot could dislodge and travel to the lungsresulting in a pulmonary embolism (PE) and death. Current treatment ofDVT includes high doses of lytic enzymes such as streptokinase andtissue plasminogen activator (tPA), sometimes augmented with mechanicalextraction (Angiojet, Trellis Infusion System). The doses of lyticenzymes are such that in many patients (particularly elderly) the riskof hemorrhage is high and poor outcomes common (A review ofantithrombotics: Leadley R J Jr, Chi L, Rebello S S, Gagnon A. JPharmacol Toxicol Methods; Contribution of in vivo models of thrombosisto the discovery and development of novel antithrombotic agents. 2000March-April; 43(2):101-16; A review of potential tPA complications:Hemorrhagic complications associated with the use of intravenous tissueplasminogen activator in treatment of acute myocardial infarction, TheAmerican Journal of Medicine, Volume 85, Issue 3, Pages 353-359 R.Califf, E. Topol, B. George, J. Boswick, C. Abbottsmith, K. Sigmon, R.Candela, R. Masek, D. Kereiakes, W. O'Neill, et al., the disclosures ofwhich are hereby expressly incorporated by reference herein). Inaccordance with several embodiments, the DVT model allows determinationof whether the magnetomotive stator system enhances the activity of tPAat the site of the thrombus such that a significantly lower dose of tPAcan be used, greatly reducing the risk of hemorrhage. Further, currentmechanical thrombolytics are known to damage endothelium. Following eachexperiment, the vessel segment is evaluated histologically forendothelial integrity.

Embodiment of a Procedure: This is a non-survival animal studyprocedure. New Zealand White rabbits (1.5-2.5 kg) are anesthetized usingKetamine 35 mg/kg, Xylazine 5 mg/kg IM and the ventral neck shaved andprepared for surgery. Mask induction using isoflurane gas may be used todeepen the anesthetic plane to allow for orotracheal intubation. In oneembodiment, once intubated, the animal is moved to the operating roomand administered isoflurane gas anesthesia (1-5%, to surgical effect)for the duration of the procedure. Heart rate, respiratory rate, bodytemperature and end-tidal CO₂ are monitored while the animal is underanesthesia. In an effort to reduce the number of animals and reduce thevariability among studies, bilateral 10-12 cm incisions are madeparamedian to the trachea and sharp/blunt dissection is used to isolatethe jugular veins. If no significant complications arise, the totalnumber of animals can be reduced accordingly.

An ultrasonic flow probe is placed on the distal portion of the isolatedvessel and baseline blood flow data is collected for 30 minutes.Following stabilization of venous flow, silk (or other braided,uncoated) suture (5 or 6-0, taper needle) can be passed transverselythrough the center of the vessel lumen at the distal aspect of the areato be occluded, and secured with a loose knot. The function of thissuture is to act as an anchor for the clot and prevent embolism. Then, aligature is placed on the proximal and distal portion of the vessel(proximal in relation to the flow probe) to occlude flow. Ultimately a 2or 3 cm segment of the vessel is isolated with ligatures. 100-200 Ubovine thrombin is administered intravenously (27-30 g needle) into thespace approximately 1 mm proximal the first ligature. The proximalligature is placed immediately following withdrawal of the thrombinneedle. The entry site of the needle is closed with a small drop ofVetbond® to prevent bleeding during the lysis procedure. The clot isallowed to mature and stabilize for 30 minutes at which time theligatures are removed and tPA or a combination of tPA with magneticnanoparticles (described above) are injected at the antegrade aspect ofthe vein (27-30 g needle, entry hole again sealed with Vetbond®). Adynamic magnetic field is applied to the location and dissolution of theclot is monitored continuously for up to 3 hours via ultrasonicflowmetry. Following re-establishment of flow the animals are euthanizedwhile still under anesthesia with an IV overdose of pentobarbital (150mpk). The experimental vessel segment and residual clot is thencollected, weighed and fixed for further analysis. Dosages of tPA usedin the endovascular obstruction model range from about 312.5 U to about5000 U.

Groups: The study is accomplished in 2 phases, Pilot and Proof ofConcept. Both phases include the procedures outlined here, but the PilotPhase utilizes only the left jugular, leaving the other a naïvehistological comparator.

Pilot Groups

1. Thrombin only, no tPA. This group will establish the baseline mass ofour thrombus and allow assessment of thrombus stability.

n=30.

2. tPA only, dose ranging to establish a fully efficacious dose (100%recanalization) n=6×3 doses=18

3. tPA only, dose ranging to establish a sub-optimal dose (either 100%effective in 25-50% of subjects, or recanalization in all subjects butonly 25-50% of flow rate). tPA is notoriously variable, so thesub-optimal dose may be difficult to find. n=3×4 doses=12

4. Device alone to establish optimum particle concentration n=3×3concentrations=9

Proof of Concept Groups

Note: “n” numbers may be combined with pilot data depending on initialdata quality, further reducing animal requirements.

1. Optimal tPA. n=6

2. Sub-optimal tPA. n=6

3. Device alone. n=6

4. Device+Optimal tPA. n=6

5. Device+sub-optimal tPA. n=6

Small Vessels: Following the completion of the thrombosis procedure inthe jugular veins, the surgical plane of anesthesia is continued and alaparotomy performed. A portion of the bowel is exteriorized and bathedin saline to prevent drying. One of the large veins in the mesentery istied off and cannulated with PE10. A mixture of iron particles andfluoroscene (12.5 mg/ml in 100 ul) is injected and photographed underblack light. This can allow the determination of whether the fluoroscenediffuses into the very small veins surrounding the bowel, and canillustrate that the magnetomotive stator system directs magneticnanoparticles to the small vasculature.

Safety: Is damage done to the endothelial lining using the magnetomotivestator system? Does it create hemolysis? In some embodiments, theendovascular obstruction model allows a determination via review of thevena cava. Following the completion of the thrombosis procedure in thejugular veins, the surgical plane of anesthesia is continued and alaparotomy performed. A 5-6 cm segment of the vena cava is isolated andall branches tied off. The vessel is tied off and cannulated with PE10.Either iron nanoparticles (12.5 mg/ml in 100 pl) or saline (100 pl) isinjected and the vessel and is magnetically controlled for 3 hours. Atthe end of 3 hours the blood is removed from the vessel segment viavenapuncture and sent for assessment of hemolysis, following euthanasiathe vessel segment is explanted for histological evaluation of theendothelium. Three experiments are performed with particles and threewithout.

Arterial Access

Using the DVT model described above, it has been demonstrated that themagnetomotive stator system significantly enhances tPA efficacy in thisrabbit model (see FIGS. 37A and 37B). Tissues have been gathered thatwere evaluated histologically. There is no damage observed to tissuewhen examined histologically.

Example 2 IV-administered Nanoparticles Can Be Collected in an In VivoLigated Rabbit Femoral Artery

New Zealand White rabbits were used as in Example 1, except the femoralartery was used. Through a 3-4 cm incision in the lower abdomen, theleft femoral artery was isolated from the iliac bifurcation to theabdominal wall, and all branches were tied off. Blood flow in the arteryand the abdominal aorta were monitored continuously with a TransonicsDoppler flow probe coupled to a Transonics T206 meter.

In this example, an acute, anesthetized rabbit model of arterialocclusion was used in which the right femoral artery was isolated andligated to simulate an occlusive thrombus and create a static bloodpool. Magnetic nanoparticles (200 mg/kg) were infused intravenously over15 minutes and collected with the magnet system. The presence of asignificant mass of nanoparticles at the ligation was confirmed for eachanimal.

Example 3 The Action of Pulling IV-Administered Nanoparticles Out of theStream Can Concentrate a Drug Faster Than Diffusion Alone

Evans Blue dye (50 mg) was infused alone over 15 minutes and co-infusedwith magnetic nanoparticles in the presence of the magnet system, usingthe rabbit model of Example 2. The advancement of the dye in theoccluded artery was captured and quantified by image analysis. Theresults demonstrated that diffusion alone quickly diminished, achieving35% penetration of a ligated vessel an hour after administration. Fulldiffusion was accomplished in three rabbits in 14, 17, and 25 minutes,respectively, using magnetic nanoparticles, whereas full diffusion wasnot possible with the dye alone. The rate of diffusion remained stronglylinear for the magnetic nanoparticles, with a volume penetration rate of4% per minute, as shown in the graph in FIG. 38. FIG. 38 illustrates agraph of the exhausted diffusion of Evan's blue dye alone versuscomplete diffusion using magnetic nanoparticles.

Example 4 Magnetic Mixing of tPA and Magnetic Nanoparticles at a Clot'sSurface Results in Faster Thrombolysis Than tPA Alone

This example used an acute anesthetized rabbit model with athrombin-induced occlusive thrombus in the jugular vein. In the example,tPA alone and tPA co-administered with magnetic nanoparticles (1.2 mg)were injected locally and the time to re-canalize the vessel wasmeasured and confirmed by a Doppler flow meter. The tPA dose was takenfrom a published source and ranged from 312U to 5000U, with 2500U beingthe standard dose. The results demonstrated 3× faster time tore-canalize with the magnet system versus tPA alone, as shown in FIG.39. Similar lysis rates were demonstrated for a 0.25× tPA dose. Thus, a0.25× tPA dose can be sufficient to achieve lysis rates in the presenceof magnetic particles, thereby reducing a tPA dose compared toadministering the tPA alone. In some embodiments, the magnetic particlesamplify the effect of a smaller concentration of tPA via a mixingmechanism which directs and/or concentrates the tPA at a desiredlocation.

Similarly, to measure the effect of the magnetic nanoparticles, thenanoparticles were administered as above with a tPA dose varying from azero-dose to 5000U. A requirement of this model was that both the tPAand the particles were to be delivered via a microcatheter near the clotin order to precisely control the dose. The results demonstrated that nolysis occurred in the presence of magnetic nanoparticles alone,confirming a lack of an abrasion action in the manipulation of themagnetic nanoparticles.

Example 5 Faster Thrombolysis Results When Magnetic Nanoparticles AreIntravenously Co-Administered with a Thrombolytic Versus theThrombolytic Alone

A common technique for forming clots in arteries was implemented. Theclot was formed near the abdominal wall (approx. 3 cm from the iliacbifurcation) by first, crushing the area to be occluded with guardedhemostats to disrupt the intima (2-3 mm segment of artery) exposingcollagen, tissue factor and other pro-thrombotics from the arterialwall, then applying critical stenosis to the crushed area using 5-0 silksuture tied with a castration knot, such that flow was reduced toapproximately 25% of the baseline flow velocity (approximately 90%reduction in lumen area). Following 3-5 closure/re-open cycles, anocclusive clot formed in 30-60 minutes. The clot was consideredocclusive by the absence of measurable blood flow for 30 minutes.

With the magnet placed above the clot and rotating at 300 rpm, magnetitenanoparticles (600 mg) were co-infused with streptokinase (30,000 U) in20 ml saline over 15 minutes (2000 U/min, 80 ml/hr), followed bystreptokinase alone at 575 U/min (7.3 ml/hr). Control animals receivedthe same streptokinase infusion without the magnet placement or magneticnanoparticles.

The vessel was considered open when flow reached 50% of thepre-occlusion stenosed value (2-2.5 ml/min). In many cases, smallexcursions in flow to 0.3-0.5 were seen during the nanoparticletreatment while the magnet was activated, but not during treatment withstreptokinase alone. The 4 treated arteries opened at 29.5, 13.4, 32 and28 minutes following the beginning of treatment. The controls wereallowed 2 hours and 1 hour respectively with no measurable flowrestoration. Interestingly, after the 1 hour streptokinase controlstudy, nanoparticles and streptokinase were co-administered and themagnet activated, resulting in the vessel opening after 29 min. For theco-administration of streptokinase and nanoparticles, the mean time forclot lysis was 26.4 min with a standard deviation of 7.4 min, and astandard error of 3.3 min. Example data from the Doppler flow-probe isshown in FIG. 40 illustrating magnetic nanoparticle-accelerated clotlysis.

Example 6 Confirmation of In Vivo Clot Lysis Ultrasound Visibility

The ability to visualize the nanoparticles under Doppler ultrasoundimaging offers limited value for stroke therapies. However, fordeep-vein thrombosis applications, such a feature would allow proceduresto be performed in procedure rooms, thus not incurring the costsassociated with an x-ray suite. Because the magnetic nanoparticlescreate flow patterns in the blood, it is possible to visualize bloodflow using Doppler imaging, even if the nanoparticles themselves couldnot be observed. The study demonstrated that complete in vivo clot lysiswas highly visible under Doppler ultrasound imaging.

Using a rabbit, a midline incision (15 cm) of the vena cava was isolatedfrom the right renal vein to the iliac bifurcation and all branchesligated. A PE10 catheter with a flame-flared tip was introduced via theleft femoral vein and advanced past the bifurcation. A ligature (4-0silk) was placed around the vena cava at the bifurcation and thecatheter retracted until the ligature trapped the flared tip. Theproximal aspect of the vena cava was then ligated immediately distalfrom the right renal vein creating an isolated, blood-filled segmentapproximately 8-9 cm long. A thrombus was formed at the proximal end ofthe segment by clamping (atraumatic vascular clamp) 1.5 cm distal theproximal ligation and injecting 50 U of thrombin (30 μl) viavenapuncture (30 g). The needle was slowly withdrawn and the puncturesite sealed with a drop of tissue adhesive. The clot was allowed tomature for 30 minutes prior to clamp removal. 12 mg of nanoparticles and5000 U of tPA were then injected (200 μl) via the femoral catheter andthe magnet started. The thrombolysis was recorded with DopplerUltrasound (SonoSite M-Turbo system). Complete clot lysis occurred in 11minutes and was highly visible under Doppler ultrasound imaging.

Example 7 In Vitro Studies: Confirmation of 2D Magnetic NanoparticleControl

As an extension to the previous examples, a bifurcated glass phantom wasobtained to investigate the ability to control the direction of thenanoparticles in two dimensions. The parent vessel is 1 mm wide with 0.5mm bifurcations. Control of the nanoparticles is depicted in FIG. 41. In(a)-(b), the nanoparticle collection is split between the bifurcations.In segment (c), the nanoparticles are retracted. In segment (d) thenanoparticles are directed down the lower branch before being againretracted in (e). The nanoparticles are directed along the upward branchin (f).

Investigations were carried out to quantify the relationship between thelytic-agent dose and the lysis rate. Two lytic agents were used in thesestudies: streptokinase and tPA. The clot recipes are summarized below.

Streptokinase Clot Recipe

The clot model used for the streptokinase dissolution test was a bovinefibrinogen/human plasminogen hybrid with clotting initiated with humanthrombin. Bovine fibrinogen from Sigma (F8630) was dissolved into a 197mM Borate buffer solution made with Sigma components (B0252, B9876,S9625). The ratio of this solution was 0.9 grams of fibrinogen to 10 mlof buffer solution. The lyophilized plasminogen and thrombin powderswere dissolved using the buffer solution. The Human plasminogen from EMDChemicals (528175-120 units) was dissolved in 600 μl of buffer to createa 0.2 units/μl solution. The Human thrombin from Sigma (T6884-1K units)was dissolved in 5 ml of buffer to create a 200 units/ml solution.Additionally, a gelatin solution was created using 100 ml of a 100 mMPotassium phosphate solution using Sigma (P5379) and de-ionized water.To this was added 0.5 grams of porcine gelatin (Sigma G2500), 0.1 gramsSodium chloride (Sigma S9625), and 0.01 grams Thimerosal (Sigma T5125).To create the clot samples, 608 μl of fibrinogen solution, 252 μl ofborate buffer, 81 μl of gelatin solution and 10.2 μl of plasminogensolution were combined in a mixing vial and gently swirled for 15seconds. The mixture was then separated into four 230 μl batches towhich 5 μl of thrombin solution was added into each batch. Thecombination was again gently swirled to mix and 100 μl of solution andwas decanted into culture tubes and incubated at 37° C. for 4 minutes topromote clotting. The dissolving solution contained the dosages inphosphate buffered saline that had been augmented with Red #40 dye inborate buffer. (0.02 g Red #40 from CK Products dissolved in 1 ml boratebuffer.) A standard dose of plasminogen was 8 μl of solution, a standarddose of magnetic nanoparticles was 6 μl of Fe₃O₄ (Cathay Pigments 1106),and a standard dose of streptokinase was 12 μl of solution (Sigma S8026of 10 units/μl of phosphate buffered saline). Volumetric balance offractional doses was made up with borate buffer solution.

Example tPA Clot Recipe

The clot model used for the tPA dissolution test was composed of humanfibrinogen and human plasminogen with clotting initiated with bovinethrombin. Human fibrinogen from EMD Chemicals (341576) was dissolvedinto a 197 mM Borate buffer solution made with Sigma components (B0252,B9876, S9625). The ratio of this solution was 1 gram of fibrinogen to11.1 ml of buffer solution. The lyophilized plasminogen and thrombinpowders were dissolved using the buffer solution. Human plasminogen fromEMD Chemicals (528175-120 units) was dissolved in 120 μl of buffer tocreate a 1 unit/μl solution. Bovine thrombin from Sigma (T6200-1K units)was dissolved in 100 μl of buffer to create a 10 units/μl solution. Agelatin solution was created using 100 ml of a 100 mM Potassiumphosphate solution using Sigma (P5379) and de-ionized water. To this wasadded 0.5 grams of porcine gelatin (Sigma G2500), 0.1 grams Sodiumchloride (Sigma S9625), and 0.01 grams Thimerosal (Sigma T5125). Asolution with tantalum nanoparticles was made to add visual contrast tothe clot. This was composed of 0.0231 g of Ta powder (AP Materials010111) in 1 ml of de-ionized water. To create the clot samples, 100 μlof fibrinogen solution, 125 μl of borate buffer, 32 μl of gelatinsolution, 25 μl of tantalum nanoparticles solution and 3 μl ofplasminogen solution were combined in a mixing vial and gently swirledfor 15 seconds. To the mixture, 5 μl of thrombin solution was added andthe combination gently swirled to mix. 100 μl of solution was decantedinto each of two culture tubes and incubated at 37° C. for 4 minutes topromote clotting. The dissolving solution contained the dosages inphosphate buffered saline. A standard dose of plasminogen was 3 μl ofsolution, a standard dose of magnetic nanoparticles was 12 μl of Fe₃O₄(Cathay Pigments 1106), and a standard dose of tPA was 32 μl of solution(EMD Chemicals 612200 of 78.125 units/μl of phosphate buffered saline).Volumetric balance of fractional doses was made up with borate buffersolution.

FIG. 42 depicts the test-tube model used to quantify the lysis rateusing both streptokinase and tPA. In the figure, the MET sample is onthe left with the magnetic nanoparticles indicated in black. The controlsample is on the right with the arrow indicating the meniscus. Bothsamples use a full dose of streptokinase. The test tubes measure about 5mm in width and the ruler is subdivided into 0.5 mm tick marks. Theartificial thrombus was intentionally constructed to be dense in orderto slow down the lysis rate. These relatively slow models made trackingthe fall of the meniscus easier for both the MET and control samples andresulted in better wall adhesion. For streptokinase, typical total METlysis times using streptokinase were under about 7 hrs. For tPA, METlysis rates were under about 4 hrs. Models in which lysis occurred inless than 1 hr resulted in clot fragmentation that made quantificationof the rate of lysis problematic. FIG. 43 depicts the relative doseresponse improvement possible with MET using streptokinase and tPA,respectively. For a relative lytic-agent dose=1, MET results in lysisabout 11.5 times faster for streptokinase and about 3 times faster fortPA (versus the control). Not captured in these plots is the result thatwhen no lytic agent is used with MET, no lysis occurs. This suggeststhat there is a rapid fall-off at relative lytic doses less than about⅛th for streptokinase and about 1/32nd for tPA. The linear fits suggestequivalent lysis rates at about 1/80th dose for streptokinase and about1/60th dose for tPA. The above work was performed using about a 0.01 Tfield at about a 5 Hz frequency, and exploratory work using fields fromabout 0.01-0.03 T and frequencies from about 1-10 Hz have shown littleimpact on these results.

Example 8 Comparing Lysis Rates and Nanoparticle Dose

An in vitro test tube study was performed to measure the effects of amagnetic nanoparticle dose with a common tPA dose. The clot recipedetailed in Example 7 was used in the model. FIG. 44 is a captured imageof the test tube setup. In the figure, the tPA dose is common across allsamples and the multipliers refer to the magnetic nanoparticle dose. Inthis study, the magnetic nanoparticle doses were exponentially reducedfrom the starting (1×) dose of 0.28 mg. Common to all samples is 625U oftPA.

Not depicted are the effects of a 1× nanoparticle dose when no tPA ispresent, which resulted in no measurable lysis. This confirms that, inaccordance with several embodiments, the technology described herein ispharmacomechanical in nature, and that the nanoparticles themselves maynot generate measurable forces on the thrombus.

FIG. 45 depicts the change in the relative lysis rate for a change inthe relative nanoparticle dose, where the 1× nanoparticle dose is thereference. As is evident, larger doses of nanoparticles result in modestgains in the lysis rate (a 0.1× dose reduces the rate by less than 8% ascompared to the 1× dose). There are several hypotheses that mightexplain this relationship. It is thought that the effectiveness of thenanoparticle dose is related to the clot's exposed surface area. Oncethe surface is saturated, increasing the nanoparticle dose offers nobenefit. As another hypothesis, once there are sufficient nanoparticlesto create a macroscopic flow pattern, then more nanoparticles may not beas effective in building stronger fluidic currents.

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the systems and methods describedherein. However, the systems and methods described and claimed hereinare not to be limited in scope by the specific embodiments hereindisclosed because these embodiments are intended as illustration ofembodiments of the systems and methods. It should be understood,however, that the embodiments are not to be limited to the particularforms or methods disclosed, but instead cover all modifications,equivalents and alternatives falling within the spirit and scope of thevarious embodiments described and the appended claims.

The ranges disclosed herein encompass any and all overlap, sub-ranges,and combinations thereof. Language such as “up to,” “at least,” “greaterthan,” “less than,” “between,” and the like includes the number recited.Numbers preceded by a term such as “about” or “approximately” includethe recited numbers. For example, “about 3 mm” includes “3 mm.” Althoughthis disclosure uses the term “nanoparticles”, this term can besubstituted with the term “particles” in many embodiments. In otherwords, it is intended that the description and disclosure relating tonanoparticles can also be applied to particles that are larger thannanoparticles (e.g., between about 1.1 μm-2 μm, 2-5 μm, 5-10 μm, 10-100μm, 100-1000 μm, and larger). Rods, which may be formed of multipleparticles (e.g., nanoparticles) can have at least one dimension (e.g.,length, height, thickness) that is 2-50,000 times greater than adimension of the particle.

1. (canceled)
 2. A method of treating a fluid obstruction in a blood vessel of a subject having at least partially occluded blood flow, the method comprising: introducing magnetic particles into a blood vessel of a subject having at least partially occluded blood flow; infusing a chemical adjunct into the subject; rotating a permanent magnet at a position outside a body of the subject at a rotation frequency, wherein the rotation of the permanent magnet generates a rotating magnetic field and a magnetic gradient sufficient to cause the magnetic particles to agglomerate into rotating stir rods that rotate at the rotation frequency within the blood vessel and travel to a location of the fluid obstruction in the blood vessel, wherein the rotating stir rods create a fluidic current within the blood vessel that causes the chemical adjunct to travel toward the fluid obstruction even though blood flow is occluded; and detecting the fluidic current created by the rotating stir rods using an ultrasound-based diagnostic imaging system, thereby tracking the infusion of the chemical adjunct in real time toward the fluid obstruction.
 3. The method of claim 2, wherein the magnetic particles comprise a contrast agent.
 4. The method of claim 2, wherein the magnetic particles are coated with a contrast agent.
 5. The method of claim 2, wherein the chemical adjunct comprises a thrombolytic drug.
 6. The method of claim 2, wherein the chemical adjunct comprises plasminogen.
 7. The method of claim 2, wherein the chemical adjunct comprises alteplase.
 8. The method of claim 2, wherein the rotation frequency is between 1 Hz and 10 Hz.
 9. The method of claim 2, wherein the magnetic particles comprise magnetite nanoparticles having a single-crystalline core with a diameter greater than 20 nm and less than 200 nm.
 10. The method of claim 2, wherein said introducing and said infusing steps are performed intravenously.
 11. The method of claim 2, wherein introducing magnetic particles into the blood vessel of the subject comprises subcutaneously injecting the magnetic particles into the subject.
 12. The method of claim 2, wherein introducing magnetic particles into the blood vessel of the subject comprises intraperitoneally injecting the magnetic particles into the subject.
 13. The method of claim 2, wherein introducing magnetic particles into the blood vessel of the subject comprises infusing the magnetic particles through micro-bore tubing.
 14. A method of treating a fluid obstruction in a low-blood-flow lumen of a subject, the method comprising: introducing magnetic particles into a low-blood-flow lumen of a subject; infusing a chemical adjunct into the subject; rotating a permanent magnet at a position outside a body of the subject at a rotation frequency, wherein the rotation of the permanent magnet generates a rotating magnetic field and a magnetic gradient sufficient to cause the magnetic particles to agglomerate into rotating stir rods that rotate at the rotation frequency within the blood vessel and travel toward a location of a fluid obstruction in the low-blood-flow lumen, wherein the rotating stir rods create a fluidic current within the low-blood-flow lumen that causes the chemical adjunct to travel to the fluid obstruction even though there is low blood flow; and detecting a location of the rotating stir rods using an imaging modality, thereby tracking the infusion of the chemical adjunct in real time into the low-blood-flow lumen.
 15. The method of claim 14, wherein the imaging modality is selected from the group consisting of: Doppler imaging, X-ray imaging, positron emission tomography imaging, magnetic resonance imaging, computed tomography imaging, and ultrasonic imaging.
 16. The method of claim 14, wherein the magnetic particles comprise a contrast agent.
 17. The method of claim 14, wherein the chemical adjunct comprises a thrombolytic drug.
 18. The method of claim 14, wherein the rotation frequency is between 1 Hz and 10 Hz, and wherein the magnetic particles comprise magnetite nanoparticles having a single-crystalline core with a diameter greater than 20 nm and less than 200 nm.
 19. The method of claim 14, wherein introducing magnetic particles into the low-blood-flow lumen of the subject comprises subcutaneously or intraperitoneally injecting the magnetic particles into the subject.
 20. The method of claim 14, wherein the magnetic particles are configured to act as contrast agents, and wherein the method further comprises determining a measure of diffusion of the chemical adjunct at the location of the fluid obstruction based on the location of the rotating stirring rods detected by the imaging modality.
 21. The method of claim 20, further comprising adjusting said infusing of the chemical adjunct based on the location of the rotating stirring rods detected by the imaging modality. 